Could aldosterone gone bad be the cause of ccsvi and ms?

A forum to discuss Chronic Cerebrospinal Venous Insufficiency and its relationship to Multiple Sclerosis.

Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Thu Nov 29, 2012 3:27 pm

Aldosterone is connected to so many ms related factors...lyndacarol's insulin resistance, a player in immune response to bacteria, a vasoconstrictor, an upregulator of vegf, a contributor to vascular fibrosis, possible inflator of sympathetic reactivity, an impairment to baroreflex, etc.

I have also noticed my ms symptoms always hype up during that time of the month (sorry guys). Aldosterone builds to a peak during luteal phase. Progesterone inhibits aldosterone action by blocking receptors but when progesterone drops dramatically at "that time," the aldosterone gets free reign until progesterone picks up again...which is when my hyped up symptoms settle down. Coincidence?

Sloppy theory but they all have to start somewhere. :p

Forgot to tie up the aldosterone-CCSVI package neatly...aldosterone can cause vascular hypertension which can and does over time damage valves. Damaged valves are implicated in CCSVI. Also, is it possible that the narrowed veins are chronically constricted due to baroreflex/sympathetic nervous system dysfunction? Do they react to baroreflex tests or other means of dilation/constriction?
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Thu Nov 29, 2012 8:23 pm

http://www.hormones.gr/99/article/article.html

Case history of a 39 year old woman who had experienced 4 years of hypertension and other symptoms. Doctors found a benign tumor that secreted high levels of aldosterone. They removed the tumor and 6 months later she experienced her first ms flare...after 4 years of exposure to elevated aldosterone.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 7:18 am

http://www.jimmunol.org/content/184/1/191.short
Aldosterone Promotes Autoimmune Damage by Enhancing Th17-Mediated Immunity

Andrés A. Herrada*,
Francisco J. Contreras*,
Natacha P. Marini*,
Cristian A. Amador†,
Pablo A. González*,
Claudia M. Cortés‡,
Claudia A. Riedel‡,
Cristián A. Carvajal*§,
Fernando Figueroa¶,
Luis F. Michea†,
Carlos E. Fardella*§ and
Alexis M. Kalergis*‖

+ Author Affiliations

*Millennium Nucleus on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas,


§Departamento de Endocrinología, Facultad de Medicina, and


‖Departamento de Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile;


†Instituto de Ciencias Biomédicas, Universidad de Chile;


‡Departamento de Ciencias Biológicas, Laboratorio de Biologia Celular y Farmacologia, Universidad Andrés Bello; and


¶Facultad de Medicina, Universidad de Los Andes, Santiago, Chile

Address correspondence and reprint requests to Dr. Alexis M. Kalergis, Millennium Nucleus on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda #340, Santiago E-8331010, Chile. E-mail addresses: akalergis@bio.puc.cl or kalergis@vtr.net


Abstract

Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8+ T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-β in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4+ T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8+ T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.


Progesterone acts as an mineralocorticoid receptor blockade. This is most likely why pregnant women enjoy MS remission. High progestorone levels in pregnancy block the action of aldosterone.

Modified citrus pectin also inhibits some aldosterone activity by binding to Galectin-3. More detail in separate MCP thread. I am not sure if it can inhibit aldosterone action as well as progesterone. Will look for more info on that.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 7:39 am

This one's for you lyndacarol :)

http://care.diabetesjournals.org/conten ... 2349.short
Insulin Resistance and Hyperinsulinemia Are Related to Plasma Aldosterone Levels in Hypertensive Patients

GianLuca Colussi, MD,
Cristiana Catena, MD, PHD,
Roberta Lapenna, MD,
Elisa Nadalini, MD,
Alessandra Chiuch, MD and
Leonardo A. Sechi, MD

+ Author Affiliations

From the Hypertension and Diabetes Unit, Division of Internal Medicine, Department of Experimental and Clinical Pathology and Medicine, University of Udine, Udine, Italy

Address correspondence and reprint requests to Leonardo A. Sechi, MD, Clinica Medica, University of Udine, Department of Experimental and Clinical Pathology and Medicine, Piazzale S. Maria della Misericordia, 1 Udine 33100, Italy. E-mail: sechi@uniud.it


Abstract

OBJECTIVE—An association between aldosterone and insulin resistance has been demonstrated in obesity and primary aldosteronism and in blacks with the metabolic syndrome. The aim of this study was to evaluate the relationship of plasma aldosterone with insulin sensitivity in white subjects.

RESEARCH DESIGN AND METHODS—In 356 patients with essential hypertension and 102 normotensive control subjects of comparable age and BMI, we measured, after discontinuation of treatment, plasma active renin, aldosterone, cortisol, glucose, insulin, and C-peptide levels and calculated markers of insulin sensitivity. Direct assessment of insulin sensitivity was obtained in a subset of 64 hypertensive patients by a hyperinsulinemic clamp.

RESULTS—Hypertensive patients had significantly greater fasting plasma insulin and C-peptide concentrations and homeostasis model assessment (HOMA) indexes than normotensive control subjects. A positive association with increasing plasma aldosterone concentrations was demonstrated for plasma glucose, insulin, C-peptides, and HOMA. Assessment of insulin sensitivity by clamp showed a significant decrease of the metabolic clearance rate of glucose with increasing aldosterone levels. Significant correlations were found between plasma aldosterone, plasma insulin, and C-peptide levels, HOMA, and glucose metabolic clearance rate. Blood pressure and plasma potassium, plasma cortisol, and renin levels, but not BMI, were also directly correlated with plasma aldosterone. Multiple regression analysis showed that HOMA, together with plasma potassium, cortisol, and renin levels, was independently correlated with plasma aldosterone.

CONCLUSIONS—This study demonstrates a direct relationship between aldosterone, insulin resistance, and hyperinsulinemia in white subjects. In patients with hypertension, this relationship might contribute to maintenance of high blood pressure and increased cardiovascular risk.


edited to add: http://atvb.ahajournals.org/content/32/2/257.abstract

Aldosterone Induces Vascular Insulin Resistance by Increasing Insulin-Like Growth Factor-1 Receptor and Hybrid Receptor

Shamshad J. Sherajee,
Yoshiko Fujita,
Kazi Rafiq,
Daisuke Nakano,
Hirohito Mori,
Tsutomu Masaki,
Taiga Hara,
Masakazu Kohno,
Akira Nishiyama,
Hirofumi Hitomi

+ Author Affiliations

From the Departments of Pharmacology (S.J.S., K.R., D.N., A.N., H.H.), Cardiorenal and Cerebrovascular Medicine (Y.F., T.H., M.K.), and Gastroenterology and Neurology (H.M., T.M.), Faculty of Medicine, Kagawa University, Kagawa, Japan.

Correspondence to Hirofumi Hitomi, MD, PhD, Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. E-mail hitomi@kms.ac.jp

Dr Sherajee and Dr Fujita contributed equally to this work.



Abstract


Objective—We previously showed that aldosterone induces insulin resistance in rat vascular smooth muscle cells (VSMCs). Because insulin-like growth factor-1 receptor (IGF1R) affects insulin signaling, we hypothesized that aldosterone induces vascular insulin resistance and remodeling via upregulation of IGF1R and its hybrid insulin/insulin-like growth factor-1 receptor.


Methods and Results—Hybrid receptor expression was measured by immunoprecipitation. Hypertrophy of VSMCs was evaluated by 3H-labeled leucine incorporation. Aldosterone (10 nmol/L) significantly increased protein and mRNA expression of IGF1R and hybrid receptor in VSMCs but did not affect insulin receptor expression. Mineralocorticoid receptor blockade with eplerenone inhibited aldosterone-induced increases in IGF1R and hybrid receptor. Aldosterone augmented insulin (100 nmol/L)-induced extracellular signal-regulated kinase 1/2 phosphorylation. Insulin-induced leucine incorporation and α-smooth muscle actin expression were also augmented by aldosterone in VSMCs. These aldosterone-induced changes were significantly attenuated by eplerenone or picropodophyllin, an IGF1R inhibitor. Chronic infusion of aldosterone (0.75 μg/hour) increased blood pressure and aggravated glucose metabolism in rats. Expression of hybrid receptor, azan-positive area, and oxidative stress in aorta was increased in aldosterone-infused rats. Spironolactone and tempol prevented these aldosterone-induced changes.


Conclusion—Aldosterone induces vascular remodeling through IGF1R- and hybrid receptor–dependent vascular insulin resistance. Mineralocorticoid receptor blockade may attenuate angiopathy in hypertensive patients with hyperinsulinemia.
Last edited by Anonymoose on Fri Nov 30, 2012 8:27 am, edited 1 time in total.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 8:22 am

Beware, certain topics cause me to react in an extremely juvenile manner. I blame MS...

For the gut bacteria/faecal transplant fans...

http://www.sciencedirect.com/science/ar ... 3179901663
Reduction of aldosterone by anaerobic bacteria: Origin of urinary 21-deoxy metabolites in man
V.D. Bokkenheuser∗,
J. Winter∗,
J.W. Honour†,
C.H.L. Shackleton, ‡
∗ Department of Pathology, St. Luke's Hospital Center, New York, NY 10025, U.S.A.
† Division of Clinical Chemistry, Clinical Research Centre, Harrow, Middlesex, England
‡ Biomedical Mass Spectrometry Resource, Space Sciences Laboratory, University of California, Berkeley CA 94720, U.S.A.

--------------------------------------------------------------------------------


Abstract

Aldosterone was incubated with pure cultures of human faecal micro-organisms and the products were analysed as methyloxime/trimethylsilyl ethers by gas chromatography/mass Spectrometry. Clostridium paraputrificum quantitatively reduced the A-ring of aldosterone to a 3α-hydroxy-5β group (tetrahydroaldosterone). In addition, aldosterone was quantitatively 21-dehydroxylated by culture no. 116 and Eubacterium lentum. Metabolism of aldosterone with mixed faecal flora yielded a single metabolite, 21-deoxy-tetrahydroaldosterone, reflecting the enzymatic action of both C. paraputrificum and culture no. 116. It is likely, therefore, that the 21-deoxymetabolites of aldosterone which have been identified in urine are formed by the action of these organisms during the passage of tetrahydroaldosterone through the gut following biliary excretion. The reduced metabolites are reabsorbed prior to urinary excretion. The specificity and high yield of the reactions carried out by these organisms suggest that they will prove useful for small scale production of reference compounds not yet commercially available, since almost all steroids with α-ketol side chain have been shown to be susceptible to transformation.


Admittedly, I'm not sure if this would reduce plasma aldosterone levels. I think "reduction" in this case refers to breakdown not reduction of levels. Oh well..a crumb for the poopy fans anyway. Your favorite bacteria can kick some aldosterone butt...if they can get to it.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 8:34 am

Aldo induced VEGF increase and evidence of Aldo's localized non-hemodynamic activity.

http://www.sciencedirect.com/science/ar ... 0507004730
Abstract

Accumulating evidence shows that aldosterone plays an important role in the pathogenesis of renal fibrosis but its mechanism has not been completely defined. Recently, exogenous administration of aldosterone significantly alleviated ischemic states in a model of femoral artery ligated rats, accompanied by an obvious enhancement of VEGF upregulation. We hypothesized that aldosterone may also regulate the expression of VEGF in the kidney. To confirm this, cultured cortical collecting duct epithelial cells (M-1 cell line) were incubated with aldosterone and control media, respectively. The pathway by which aldosterone regulates VEGF expression was tested by the administration of spironolactone, a specific mineralocorticoid receptor (MR) antagonist. VEGF expression was detected by immunofluorescence staining, ELISA, Western blot and RT-PCR. Aldosterone induced an elevation of VEGF excretion in a time- and dose-dependent manner. Western blotting showed a 1.4-fold elevation in cytosolic VEGF expression following aldosterone (10− 8 M) incubation for 48 h (p < 0.01). After aldosterone (10− 7 M) incubation for 48 h, the mRNA level of VEGF164 and VEGF120 showed 1.8- and 1.7-fold increases, respectively (p < 0.01). This upregulation was almost completely blocked by spironolactone as shown both by mRNA levels and cytosolic protein levels. In addition, the mRNA of aldosterone receptor was detected in M-1 cells. We demonstrated for the first time that aldosterone induced VEGF expression in M-1 cells, an effect mediated by classic mineralocorticoid receptor. This finding provides experimental evidence for the local non-hemodynamic action of aldosterone.

and http://www.sciencedirect.com/science/ar ... 8911001996
Aldosterone increases VEGF-A production in human neutrophils through PI3K, ERK1/2 and p38 pathways
Cécile Walczak,
Fanny Gaignier,
Alexandre Gilet,
Feng Zou,
Simon N. Thornton,
Armelle Ropars,
University of Henri Poincaré, U961 UHP-INSERM, Vandoeuvre-les-Nancy, France

Abstract

Aldosterone is now recognised as an important actor in inflammation processes. Neoangiogenesis plays a crucial role in this complex process and immune cells, such as neutrophils, appear to be able to secrete different forms of (pro)angiogenic molecules, especially VEGF-A. The present work was undertaken to investigate whether aldosterone was able to regulate VEGF-A production in human neutrophils. The HL-60 (progranulocytic) cell line and human polymorphonuclear leukocytes were incubated for different time periods with aldosterone. Total cellular RNA extraction, submitted to reverse transcription and real time semi-quantitative PCR, was used to study VEGF-A mRNA expression. Cell supernatants were collected and ELISA tests were performed to analyse VEGF-A protein production. Aldosterone increased VEGF-A mRNA and protein expression in a dose- and time-dependent manner in both cell types. Inhibitors of PI3 kinases, ERK1/2, and to a lesser extent of p38 MAPK, decreased this aldosterone-induced immune cell activation. Western-blot performed with HL-60 cells confirmed that ERK1/2 and p38 MAPK pathways were stimulated by aldosterone. Mineralocorticoid receptors are implicated in this VEGF-A up-regulation because HL-60 cells pre-treated with spironolactone, an aldosterone receptor antagonist, diminished the effects of aldosterone. Aldosterone was also able to increase VEGF-A production of phagocytic cells such as neutrophils. These results suggest that this hormone could play an active role in the neovascularisation process by favouring entry of plasma proteins and fluids into the vascular wall, cell proliferation and tissue rebuilding.


like fibrinogen...
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 8:54 am

http://cardiovascres.oxfordjournals.org ... 4/663.full

Review of aldosterone- and angiotensin II-induced target organ damage and prevention


Abstract

Aldosterone is well recognized as a cause of sodium reabsorption, water retention, and potassium and magnesium loss; however, it also produces a variety of other actions that lead to progressive target organ damage in the heart, vasculature, and kidneys. Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. Although angiotensin II has been considered the major mediator of cardiovascular damage, increasing evidence suggests that aldosterone may mediate and exacerbate the damaging effects of angiotensin II. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce plasma aldosterone levels initially, aldosterone rebound, or ‘escape’ may occur during long-term therapy. Therefore, aldosterone blockade is required to reduce the risk of progressive target organ damage in patients with hypertension and heart failure. This may be achieved nonselectively with spironolactone or with use of the selective aldosterone blocker eplerenone. While both agents have been demonstrated to be effective antihypertensive agents, eplerenone may produce improved target organ protection as witnessed in a variety of clinical settings, without the antiandrogenic and progestational effects commonly observed with spironolactone.....


Image

....
2.4 Endothelial dysfunction and arterial compliance

Several mechanisms have been proposed to explain the negative effects of aldosterone on vascular smooth muscle cells (VSMC), endothelial cells, and vascular matrix in hypertensive individuals. Although these proposed mechanisms have merit, one in particular has gained widespread acceptance. Kornel [10] proposed that glucocorticoids and mineralocorticoids, mediated through receptors, control the contractility of VSMC through increasing transport capacities for Na+ and Ca2+. The reduction of endothelium-dependent vasodilation by acetylcholine, through aldosterone inhibition of nitric oxide release, has been proposed as the mechanism by which endothelial dysfunction occurs [34]. The untoward effects of aldosterone on the vascular matrix have been established to be caused by a disproportionate increase in collagen content or fibrosis due to long-term elevations in circulating mineralcorticoids [34].

Aldosterone-induced profibrotic effects lead to reduced arterial compliance and impaired baroreflex activity and, consequently, to impaired autonomic control of cardiac and vascular function in patients with hypertension and heart failure [34]. In heart failure patients, chronically treated with captopril, furosemide, digoxin, and aspirin, plasma aldosterone concentrations correlated inversely with arterial compliance in the aorta and its major proximal branches [35]. A similar correlation was observed in patients with primary aldosteronism. The reduced arterial compliance was further correlated with baroreflex function [36].
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby cheerleader » Fri Nov 30, 2012 9:07 am

aldosterone is one of many endothelial disrupters--and we can add it to the list as an important hormonal player.
Thanks, anonymoose. Great papers.
But it's not just one thing. Low vitamin D levels and high cortisol levels are 2 known hormonal factors---so is smoking, EBV virus, Lyme bacteria, highly saturated fats, high glucose intake heavy metals, diesel particulates------
which are a few of the factors being studied by BNAC and other groups.

cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 9:35 am

cheerleader wrote:aldosterone is one of many endothelial disrupters--and we can add it to the list as an important hormonal player.
Thanks, anonymoose. Great papers.
But it's not just one thing. Low vitamin D levels and high cortisol levels are 2 known hormonal factors---so is smoking, EBV virus, Lyme bacteria, highly saturated fats, high glucose intake heavy metals, diesel particulates------
which are a few of the factors being studied by BNAC and other groups.

cheer


Thanks cheer,

I'm still curious about the relationship between other contributing factors and aldo so I'm going to keep digging. I found a paper on vitamin d and RAAS, will post momentarily.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 9:37 am

http://www.ibridgenetwork.org/uctech/uchi-1709
Renin-angiotensin-aldosterone System: Target of Vitamin D Protection and Therapy

University of Chicago
posted on 06/01/2009

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Pharmaceutical compositions and methods for preventing, treating, and delaying diseases with an overactive renin-angiotensin system by administering Vitamin D and its analogues, optionally with ACE inhibitors, angiotensin inhibitors or aldosterone blockers.

Suggested Uses

Vitamin D, its analogues, and derivatives are novel agents alone or in combination with ACE inhibitors, angiotensin inhibitors, or aldosterone blockers to prevent, treat, or delay diseases including cardiovascular, cerebrovascular, and peripheral vascular diseases. These pharmaceutical compositions and methods are especially useful for chronic kidney disease, heart failure,diabetic nephropathy, cardiomyopathy, atherosclerosis, myocardial infarction, and cerebrovascular accidents.

Advantages

While ACE inhibitors and angiotensin receptor blockers result in compensatory increases in renin expression, Vitamin D supresses the expression of renin resulting in effective therapy for diseases with an overactive renin-angiotensin system. Vitamin D analogs and derivatives are able to provide the therapeutic effects without inducing hypercalcemia.


Innovation Details



Detailed Description

The renin-angiotensin system is involved in blood pressure, electrolyte and volume homeostasis. Inappropriate activation of the renin-angiotensin system may lead to infarction, congestive heart failure, progressive atherosclerosis and renal failure. Renin is a rate-limiting component of the renin-angiotensin system. Renin cleaves angiotensin I from angiotensinogen, which is then converted to angiotensin II byt angiotensin-converting enzyme. Angiotensin II, through binding to its receptors, exerts diverse actions that affect the electrolye, volume, and blood pressure. Inappropriate stimulation of the renin-angiotensin system has been associated with hypertension, heart attack and stroke. Vitamin D is a negative regulator of renin expression in vivo. Increases in serum vitamin D levels lead to suppression of renin expression. Vitamin D is an endocrine suppressor for renin biosynthesis. Vitamin D analogues with less calcemic effect and higher potency then Vitamin D can be used for suppressing renin biosynthesis. Treatment of patients with cardiovascular disease by administration of a therapeutically effective amount of a Vitamin D analog or Vitamin D receptor activator is expected to be advantageous for effective reduction of renin expression, decreased inflammation and improved cardiac function. Since ACE inhibitors, angiotensin II inhibitors, and aldosterone receptor blockers have different efficacies and affect the body through different pathways than Vitamin D does, compositions may include one of these agents in therapeutically effective amounts which are well known to inhibit activation of the renin-angiotensin system and readily available.


another vitamin D paper

http://www.ncbi.nlm.nih.gov/pubmed/21718915


Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans.

Al Mheid I, Patel R, Murrow J, Morris A, Rahman A, Fike L, Kavtaradze N, Uphoff I, Hooper C, Tangpricha V, Alexander RW, Brigham K, Quyyumi AA.


Source

Emory University School of Medicine, Atlanta, Georgia 30322, USA.


Abstract

OBJECTIVES:

The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults.

BACKGROUND:

Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function.

METHODS:

We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness.

RESULTS:

Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (β = 0.1, p = 0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09, p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02).

CONCLUSIONS:

Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.

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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Fri Nov 30, 2012 11:55 am

Hypertension/high blood pressure NOT necessary for Aldosterone to cause vascular damage. Maybe this is how it sneaks by and does it's damage while we are none the wiser...

http://hyper.ahajournals.org/content/46/1/29.full

Editorial Commentaries

Aldosterone Promotes Endothelial Dysfunction Via Prostacyclin Independent of Hypertension

Fruzsina K. Johnson,
Robert A. Johnson,
William Durante

+ Author Affiliations

From the Tulane Hypertension and Renal Center of Excellence (F.K.J., R.A.J.), and Department of Physiology, Tulane University Health Sciences Center, New Orleans, La; and the Michael E. DeBakey VA Medical Center (W.D.), and Departments of Medicine and Pharmacology, Baylor College of Medicine, Houston, Tex.

Correspondence to Fruzsina K. Johnson, MD, Assistant Professor, Department of Physiology, Tulane University Health Sciences Center, 1430 Tulane Avenue, SL-39, New Orleans, LA 70112. E-mail Fruzsi123@aol.com

The renin-angiotensin-aldosterone system plays a key role in the regulation of blood pressure and water/electrolyte homeostasis. Classically, angiotensin II causes arteriolar vasoconstriction and increases aldosterone levels, whereas aldosterone promotes sodium and water reabsorption and potassium secretion via renal mineralocorticoid receptors. It is now well-accepted that inappropriate activation of the renin-angiotensin-aldosterone system not only increases blood pressure but also can play an important role in end-organ damage. Although Selye et al have demonstrated that administration of a mineralocorticoid combined with sodium promotes malignant hypertension and end-organ damage,1 subsequent clinical and experimental studies have focused on the pathological effects of angiotensin II, rather than aldosterone, and demonstrated that angiotensin-converting enzyme inhibitors, as well as angiotensin II receptor antagonists, confer significant cardiovascular protection.

Recent discoveries have revolutionized our view of aldosterone and its biological actions, and identified mineralocorticoids as important mediators of cardiovascular injury.2,3 The demonstration of rapid aldosterone effects challenged the exclusive role of mineralocorticoid receptor-mediated genomic actions in aldosterone signaling.4 Furthermore, it is now well-established that aldosterone can exert effects in nonepithelial and extrarenal tissues.2 Moreover, mineralocorticoids not only exert effects on extrarenal tissues but also can be synthesized outside the adrenal cortex.5 Aldosterone has now been shown to promote cardiovascular inflammation, endothelial dysfunction, and fibrosis.2 Furthermore, the effects of aldosterone can be independent of blood pressure, because mineralocorticoid receptor blockade can confer cardiovascular protection without lowering the blood pressure.6 In the light of these advancements, recent clinical trials have shown the cardiovascular protective benefits of mineralocorticoid receptor blockade.7

In this issue of Hypertension, an interesting article by Blanco-Rivero et al8 extends our understanding of aldosterone-mediated end-organ damage by demonstrating the role of prostacyclin in aldosterone-induced endothelial dysfunction. The authors demonstrate that chronic administration of aldosterone does not affect blood pressure but promotes endothelial dysfunction in normotensive Wistar Kyoto (WKY) and in spontaneously hypertensive rats (SHR). This supports previous observations that aldosterone promotes cardiovascular injury without raising the blood pressure, and that mineralocorticoid receptor antagonism can exert significant protective effects without lowering the blood pressure.6

It should be noted, however, that the authors used tail-cuff plethysmography to measure the blood pressure, which can be less accurate compared with direct inline measurements. Thus, their results do not exclude the possibility of aldosterone promoting subtle changes or perhaps altering the diurnal variations in blood pressure. In fact, another article9 has showed that the renoprotective effect of aldosterone blockade depends on its ability to lower the blood pressure. Though this issue needs further clarification, it appears that aldosterone can promote vascular injury without major changes in blood pressure, and conversely aldosterone receptor blockade can exert cardiovascular protection without normalizing the blood pressure.

The authors also investigate the role of prostaglandins in aldosterone-mediated endothelial dysfunction. They show that aldosterone increases vascular cyclooxygenase-2 protein expression in both WKY and SHR. By using selective and nonselective cyclooxygenase-2 inhibitors, they can improve endothelial dysfunction in both strains, indicating the participation of cyclooxygenase-2 metabolites in the attenuated endothelium-dependent vasodilation in both strains.

With respect to eicosanoid metabolism, the most commonly accepted cyclooxygenase-derived vasoconstrictor metabolite is thromboxane A2. In this study, the authors showed that a thromboxane receptor antagonist improved endothelium-dependent relaxation in both aldosterone-treated SHR and WKY, but a thromboxane synthesis inhibitor had no affect. Furthermore, they could not show increased release of thromboxane A2 metabolites from vessels with aldosterone-induced endothelial dysfunction. Collectively, these data challenge the primary role of thromboxane A2 in aldosterone-induced endothelial dysfunction.

Numerous studies demonstrated that prostacyclin (PGI2) promotes vasodilation in various vascular beds. However, it is often forgotten that prostacyclin can also promote vasoconstriction via thromboxane receptors. As an additional novel aspect of this study, the authors demonstrate that aldosterone-induced endothelial dysfunction is associated with increased vascular release of prostacyclin metabolites and inhibition of prostacyclin synthesis can improve endothelium-dependent relaxation. Therefore, they conclude that increased prostacyclin production contributes to aldosterone-induced endothelial dysfunction.

Interestingly, a previous study suggested that a rapid nongenomic vascular effect of aldosterone is vasodilation.10 This vasodilatory effect is most likely caused by increased nitric oxide synthase activation, but the role of vasodilatory prostanoids could not be ruled out. Thus it appears that long-term administration of aldosterone exerts opposite effects on vascular endothelial function, perhaps caused by vascular inflammation. This represents an interesting diversity in the short-term versus long-term actions of aldosterone and underlines the pathological significance of chronic inappropriate activation of the renin-angiotensin-aldosterone system in vascular injury.

The use of aortic rings to assess vascular reactivity in the study by Blanco-Rivero et al8 potentially limits its applicability to changes in vascular resistance or blood flow. The aorta is a large conduit vessel and as such does not appreciably affect vascular resistance. However, in large conduit vessels endothelial dysfunction has been suggested to contribute to atherosclerosis. As such, these studies could have implications to human macrovascular disease.

It should also be mentioned that the authors specifically adjusted the tension of the aortic ring preparations to eliminate the initial differences in vascular reactivity between the normotensive WKY and hypertensive SHR strains. Though this makes the preparations more comparable for easier demonstration of the aldosterone effects, it is may not accurately reflect their in vivo state. It is possible that in vivo when the aortas are subjected to altered tensions caused by the differences in blood pressure, the aldosterone-induced endothelial dysfunction affects vascular reactivity to a different degree.

Collectively, this interesting study demonstrates that aldosterone promotes endothelial dysfunction independent of blood pressure. They also show that aldosterone-induced endothelial dysfunction is most likely mediated by increased cyclooxygenase-2–derived prostacyclin-mediated vasoconstriction in normotensive and hypertensive animals. Clearly, this original study contributes to our understanding in the role of aldosterone in vascular injury.

Finally, in the Perspectives section of their article, the authors hypothesize that cyclooxygenase-2 inhibitors could be used to restore endothelial function and prevent vascular injury. Whereas this is a logical extension of their current data, in the light of other serious side effects of cyclooxygenase-2 inhibitors in patients with cardiovascular disease and the current controversy over the use of cyclooxygenase-2 inhibitors in these patients, this approach currently may be inadvisable. Further studies are needed to examine the role of cyclooxygenase-2 metabolites in vascular injury and establish safer methods to limit their production. However, this does not detract from the pathophysiological significance of these findings.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby lyndacarol » Fri Nov 30, 2012 7:47 pm

Great work, Anonymoose! I think you are really onto something. And thanks especially for the post on insulin resistance/hyperinsulinemia.
My hypothesis: excess insulin (hyperinsulinemia) plays a major role in MS, as developed in my initial post: http://www.thisisms.com/forum/general-discussion-f1/topic1878.html "Insulin – Could This Be the Key?"
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Sat Dec 01, 2012 8:35 am

From previous post...
http://www.jimmunol.org/content/184/1/191.short
Aldosterone Promotes Autoimmune Damage by Enhancing Th17-Mediated Immunity

Abstract

Excessive production of aldosterone leads to the development of hypertension and cardiovascular disease by generating an inflammatory state that can be promoted by T cell immunity. Because nature and intensity of T cell responses is controlled by dendritic cells (DCs), it is important to evaluate whether the function of these cells can be modulated by aldosterone. In this study we show that aldosterone augmented the activation of CD8+ T cells in a DC-dependent fashion. Consistently, the mineralocorticoid receptor was expressed by DCs, which showed activation of MAPK pathway and secreted IL-6 and TGF-β in response to aldosterone. In addition, DCs stimulated with aldosterone impose a Th17 phenotype to CD4+ T cells, which have recently been associated with the promotion of inflammatory and autoimmune diseases. Accordingly, we observed that aldosterone enhances the progression of experimental autoimmune encephalomyelitis, an autoimmune disease promoted by Th17 cells. In addition, blockade of the mineralocorticoid receptor prevented all aldosterone effects on DCs and attenuated experimental autoimmune encephalomyelitis development in aldosterone-treated mice. Our data suggest that modulation of DC function by aldosterone enhances CD8+ T cell activation and promotes Th17-polarized immune responses, which might contribute to the inflammatory damage leading to hypertension and cardiovascular disease.

Aldostersone enhances cd8 tcell activation. Cd8 tcells disrupt BBB....
http://www.jimmunol.org/content/189/4/1937.abstract
CD8 T Cell-Initiated Blood–Brain Barrier Disruption Is Independent of Neutrophil Support

Holly L. Johnson*,†‡,
Yi Chen§,
Fang Jin†,
Lisa M. Hanson†,
Jeffrey D. Gamez*,
Istvan Pirko* and
Aaron J. Johnson*,†

+ Author Affiliations

*Department of Neurology, Mayo Clinic, Rochester, MN 55905;
†Department of Immunology, Mayo Clinic, Rochester, MN 55905;
‡Neurobiology of Disease Graduate Program, Mayo Graduate School, Rochester, MN 55905; and
§Department of Neurology, University of Cincinnati, Cincinnati, OH 45267
Address correspondence and reprint requests to Dr. Aaron J. Johnson, Department of Immunology, Mayo Clinic, Guggenheim 411C, 200 First Street SW, Rochester, MN 55905. E-mail address: Johnson.Aaron2@mayo.edu

Abstract

Blood–brain barrier (BBB) disruption is a common feature of numerous neurologic disorders. A fundamental question in these diseases is the extent inflammatory immune cells contribute to CNS vascular permeability. We have previously shown that CD8 T cells play a critical role in initiating BBB disruption in the peptide-induced fatal syndrome model developed by our laboratory. However, myelomonocytic cells such as neutrophils have also been implicated in promoting CNS vascular permeability and functional deficit in murine models of neuroinflammatory disease. For this reason, we evaluated neutrophil depletion in a murine model of CD8 T cell-initiated BBB disruption by employing traditionally used anti-granulocyte receptor-1 mAb RB6-8C5 and Ly-6G–specific mAb 1A8. We report that CNS-infiltrating antiviral CD8 T cells express high levels of granulocyte receptor-1 protein and are depleted by treatment with RB6-8C5. Mice treated with RB6-8C5, but not 1A8, display: 1) intact BBB tight junction proteins; 2) reduced CNS vascular permeability visible by gadolinium-enhanced T1-weighted magnetic resonance imaging; and 3) preservation of motor function. These studies demonstrate that traditional methods of neutrophil depletion with RB6-8C5 are broadly immune ablating. Our data also provide evidence that CD8 T cells initiate disruption of BBB tight junction proteins and CNS vascular permeability in the absence of neutrophil support.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby Anonymoose » Sat Dec 01, 2012 9:23 am

The next step in the aldosterone-cd8 tcell BBB breaching scheme--VEGF

http://www.jimmunol.org/content/184/2/1031.abstract
CD8 T Cell-Initiated Vascular Endothelial Growth Factor Expression Promotes Central Nervous System Vascular Permeability under Neuroinflammatory Conditions

Georgette L. Suidan*†,
Jonathan W. Dickerson*†,
Yi Chen†,
Jeremiah R. McDole*†,
Pulak Tripathi‡,
Istvan Pirko*†,
Kim B. Seroogy*† and
Aaron J. Johnson*†

+ Author Affiliations
*Neuroscience Graduate Program and
†Department of Neurology, University of Cincinnati College of Medicine; and
‡Division of Immunobiology, Cincinnati Children's Hospital, Cincinnati, OH 45267
Address correspondence and reprint requests to Dr. Aaron J. Johnson, The Waddell Center for Multiple Sclerosis, 231 Albert Sabin Way, Medical Sciences Building, Room 7011, Academic Health Center, Cincinnati, OH 45267. E-mail address: johna4@uc.edu


Abstract

Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine model of CD8 T cell-mediated CNS vascular permeability using a variation of the Theiler’s murine encephalomyelitis virus system traditionally used to study multiple sclerosis. Previously, we demonstrated that CD8 T cells have the capacity to initiate astrocyte activation, cerebral endothelial cell tight junction protein alterations and CNS vascular permeability through a perforin-dependent process. To address the downstream mechanism by which CD8 T cells promote BBB dysregulation, in this study, we assess the role of vascular endothelial growth factor (VEGF) expression in this model. We demonstrate that neuronal expression of VEGF is significantly upregulated prior to, and coinciding with, CNS vascular permeability. Phosphorylation of fetal liver kinase-1 is significantly increased early in this process indicating activation of this receptor. Specific inhibition of neuropilin-1 significantly reduced CNS vascular permeability and fetal liver kinase-1 activation, and preserved levels of the cerebral endothelial cell tight junction protein occludin. Our data demonstrate that CD8 T cells initiate neuronal expression of VEGF in the CNS under neuroinflammatory conditions, and that VEGF may be a viable therapeutic target in neurologic disease characterized by inflammation-induced BBB disruption.
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Re: Could aldosterone gone bad be the cause of ccsvi and ms?

Postby cheerleader » Sat Dec 01, 2012 10:03 am

Looking at the cellular factors in the breakdown of the cerebral endothelium is certainly a worthwhile pursuit, and there are labs around the world doing this. But it's important to understand that Dr. Zamboni's theory involves the mechanisms of shear stress, which are hindered by venous reflux, venous congestion and endothelial dysfunction.

This process breaks down the tight junctions of endothelial cells, and allows plasmic particles access into brain tissue. Inhibiting these plasmic particles is one way to solve the problem of a permeable BBB....but understanding the mechanistic nature of blood flow, and the importance of laminer shear stress is another.

BBB endothelial cells in vivo are continuously exposed to laminar shear stress to which they respond by structural (cell orientation with flow direction; redistribution of cell fibers and flattening) and functional remodeling showing significant evidences of differentiation [21-24].

One of the main functions of the BBB is shielding of the brain from unwanted and potentially harmful substances. Tight junction protein complexes provide a mechanical means to seal the paracellular pathways between adjacent endothelial cells [8,24]. Our study shows that exposure to flow increases the RNA levels of genes encoding for a variety of tight junctional proteins (see Figure 1A) including the intracellular scaffold proteins Zonula occludens-1 (ZO1) and 2 (ZO-2) which link the junctional molecules claudin and occludin to intracellular actin and the cytoskeleton. Claudin 3, 5 and actin gene espression were also upregulated by the exposure to laminar shear stress thus strongly suggesting that acting as a key regulator of TJ expression. In addition to TJ protein upregulation we also found a significant increase the RNA and protein levels of several cadherins. These are a class of type-1 transmembrane proteins which play important roles in cell adhesion, through the formation of adherens junctions. Our data showed the up-regulation of N-, P- and VE-cadherin. We also observed an increase in the RNA and protein levels of E-cadherin. However, even though the upregulation of E-cadherin (commonly though not exclusively expressed in epithelial cells [25,26]) was statistically significant; its overall RNA and total protein expression levels were very modest in comparison to that of the other adherens junction components.

The result is the formation of tight barrier with high trans-endothelial electrical resistance that can efficiently discriminate the passage of substances according to their permeability coefficient. In the absence of intraluminal flow despite the presence of abluminal astrocytes the resulting barrier is much less stringent and does not provide selective permeability (Figure 1D). This demonstrates that glial stimuli are important but not sufficient to establish a functional BBB and that exposure to flow provides the missing modulatory element to enable BBB properties.

http://www.biomedcentral.com/1471-2202/12/40

Flow maintains the BBB. Hypoperfusion damages the BBB. Dr. Zamboni's theory is suggesting that we can we increase perfusion, shear stress and cerebral endothelial function by repairing venous malformations and improving venous return. Which is stepping back from the cellular discussion, and looking at the mechanism.
Flow.
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dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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