This Is MS Multiple Sclerosis Knowledge & Support Community

I know that MMPs (metalloproteases in matrix) have been discussed here in regard to MS, but… do you think I could find any threads today?!!

Last week, I heard mention of this MMP-9 and-8 research being done at the University of Notre Dame in regard to diabetic wound healing. I found it interesting and thought you might too:

http://news.nd.edu/news/43981-notre-dam ... d-healing/

hi lyndacarol, i know this is switching your thread up a bit but thought since your subject about diabetic wound healing might have caught the eye of someone in need and they may not be aware that hyperbaric oxygen chamber treatments can be very effective. i think it is fda approved for wound healing. getting a dr. to prescribe and availability is the trick. luckily for an acquaintenance of mine with juvenille diabetias and now 41 had lost toes and the foot was next to go it wasn't healing. the dr. got her in and it healed good and also seemed to help over all. a shame it's not used and promoted by more dr.'s and more don't seem aware. very pricey to self pay.

http://www.hopkinsmedicine.org/healthli ... ric_oxygen

lyndacarol wrote:I know that MMPs (metalloproteases in matrix) have been discussed here in regard to MS, but… do you think I could find any threads today?!!

Several of JackD's posts discuss matrix metalloproteases. Did you try searching for them?

http://www.thisisms.com/forum/search.php

jackD is back with a new "better" computer that works!

I have lots of info MMP-9s. This posting in the AVONEX section contains most of my best.
.
http://www.thisisms.com/forum/avonex-f5/topic4186.html

I also have some full text stuff in the sky.

http://home.ix.netcom.com/~jdalton/

jackD

P.S Check MMP-9 at NIH-NLM http://www.ncbi.nlm.nih.gov/ Once there CLICK ON PUBMED and then type MMP-9 and search.

you can also google mmp9 content on the site like so:

https://www.google.ca/#q=mmp-9+site:www.thisisms.com

then you can use the search tools to filter by time frame

so in the last year there are these interesting results

https://www.google.ca/#q=mmp-9+site:www ... &tbs=qdr:y

some interesting hit excerpts:
-Serum MMP-2 and MMP-9 are elevated in different multiple sclerosis subtypes (june)
-Omega-3 FA significantly decreased MMP-9 levels in RRMS and may act as an immune-modulator that has potential therapeutic benefit in MS patients (april)
-Unbalanced MMP activity promotes atherosclerotic processes (jul)

for this search I took off the time filter and added a zinc search term

https://www.google.ca/#q=mmp-9+zinc+sit ... isisms.com

pulled this bit from a 2010 chat i had w/ jack on the mmp-9 subject

http://www.thisisms.com/forum/natural-a ... tml#p87026
Zinc deficiency impairs wound healing of colon anastomosis in rats
http://www.springerlink.com/content/b123620751602861/
"Conclusions Our study constitutes the known negative effect of zinc deficiency on wound healing. Zinc deficiency significantly increased the activity of MMPs (2, 9, and 13), caused a reduced collagen type I/III ratio, and delayed cell proliferation and quality of intestinal wound healing."

interesting aside .. I read recently that omega 3s are protective against the effects of zinc deficiency

Yep! Lowering those nasty MMP-9s is a real good idea.

jackD


1: Curr Pharm Biotechnol. 2008 Feb;9(1):34-46.

Matrix metalloproteinase-9/gelatinase B is a putative therapeutic target of chronic obstructive pulmonary disease and multiple sclerosis.

Muroski ME, Roycik MD, Newcomer RG, Van den Steen PE, Opdenakker G, Monroe HR, Sahab ZJ, Sang QX.
Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306, USA.

Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes involved in an array of physiological and pathological processes from development, morphogenesis, reproduction, wound healing, and aging to inflammation, angiogenesis, neurological disorders, and cancer cell invasion and metastasis. The imbalance between MMP activity and the inhibitory action of tissue inhibitors of metalloproteinases (TIMPs) are implicated in multiple diseases. Secreted in the body in a latent form, upon activation MMP-9 (gelatinase B) acts on many inflammatory substrates, and thus is suspected of contributing to the progression of cardiovascular disease, rheumatoid arthritis, and the subjects of this review, chronic obstructive pulmonary disease (COPD) and multiple sclerosis (MS). COPD is the fourth most common cause of death in the United States. In COPD, increased expression of MMP-9 by inflammatory cells e.g. neutrophils and macrophages is correlated with a variety of processes that cause lung damage. MMP-9 is also important in cytokine and protease modulation; it degrades the serine protease inhibitor alpha(1)-antitrypsin, which thus may lead to lung destruction.

MS affects approximately 400,000 Americans and over a million people worldwide. Upregulation of MMP-9 increases the permeability of the blood brain barrier (BBB), facilitates the infiltration of leukocytes into the central nervous system, and causes myelin sheath degradation and neuronal damage. Early stage clinical trials have shown promising results when MMP-9 is inhibited in MS. These observations lead to the hypothesis that MMP-9 is a potential drug target for both COPD and MS and further development of highly potent and specific MMP-9 inhibitors is warranted.

PMID: 18289055 [PubMed - in process]

MMPs -where the good guys go bad

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

In MS it is the MMP-9s that go on rampage and do lots of damage the CNS and myelin.

jackD


Semin Cell Dev Biol. 2008 Feb;19(1):42-51. Epub 2007 Jun 19.

MMPs in the central nervous system: where the good guys go bad.

Agrawal SM, Lau L, Yong VW.

Hotchkiss Brain Institute and the Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.

Abstract
Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS. We emphasize the regulation of neurogenesis and oligodendrogenesis by MMPs during CNS development, and highlight physiological roles of MMPs in the healthy adult CNS, such as in synaptic plasticity, learning and memory.

Nonetheless, MMPs as "the good guys" go bad in neurological conditions, likely aided by the sudden and massive upregulation of several MMP members.

We stress the necessity of drawing a fine balance in the treatment of neurological diseases, and we suggest that MMP inhibitors do have therapeutic potential early after CNS injury.

PMID: 17646116 [PubMed - indexed for MEDLINE]
.
.
Things that reduce MMP-9s (AKA gelatinase B)

***NOTE*** ( gelatinase B = MMP-9) ***NOTE***

QUERCETIN..........................REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/18926575?


VIT D3 .................................REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/12454321?


RESVERATROL (Grape Skin Extract) ...REDUCES MMP-9s
(NOT GRAPE SEED EXTRACT)

http://www.ncbi.nlm.nih.gov/pubmed/14627504?


GREEN TEA EXTRACT(EGCGs)... REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/10719174?


ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid) ... REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/12458042?


NAC N-Acetyl-L-Cysteine .......REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/12679464?


STATIN DRUGS (i.e Zocor) .....REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/12370451?


Omega-3s (ie Fish oil) ...........REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/19171471?


Minocycline/Doxycycline.........REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/10415728?


Curcumin.............................REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/10510448?


Pycnogenol (Pine bark extract)..REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/14990359?


Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES MMP-9s

http://www.ncbi.nlm.nih.gov/pubmed/15792947?


Interferon Betas 1a/1b...........REDUCES MMP-9s

(of course Steroids ....REDUCES MMP-9s)

Due to a lack of enzymes that are necessary for the proper metabolism of vitamin B12, patients with MS have elevated levels of an amino acid called "homocysteine". I posted a great deal on its involvement in the MS disease process on this thread. http://www.thisisms.com/forum/general-d ... 22806.html


Homocysteine activates MMP-9. Here is the conclusion from the following study: "These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation."


Am J Physiol Heart Circ Physiol. 2006 Mar;290(3):H1206-13. Epub 2005 Oct 28.
Homocysteine causes cerebrovascular leakage in mice.
Lominadze D, Roberts AM, Tyagi N, Moshal KS, Tyagi SC.




"Elevated plasma homocysteine (Hcy) is associated with cerebrovascular disease and activates matrix metalloproteinases (MMPs), which lead to vascular remodeling that could disrupt the blood-brain barrier. To determine whether Hcy administration can increase brain microvascular leakage secondary to activation of MMPs, we examined pial venules by intravital video microscopy through a craniotomy in anesthetized mice. Bovine serum albumin labeled with fluorescein isothiocyanate (BSA-FITC) was injected into a carotid artery to measure extravenular leakage. Hcy (30 microM/total blood volume) was injected 10 min after FITC-BSA injection. Four groups of mice were examined: 1) wild type (WT) given vehicle; 2) WT given Hcy (WT + Hcy); 3) MMP-9 gene knockout given Hcy (MMP-9-/- + Hcy); and 4) MMP-9-/- with topical application of histamine (10(-4) M) (MMP-9-/- + histamine). In the WT + Hcy mice, leakage of FITC-BSA from pial venules was significantly (P < 0.05) greater than in the other groups. There was no significant leakage of pial microvessels in MMP-9-/- + Hcy mice. Increased cerebrovascular leakage in the MMP-9-/- + histamine group showed that microvascular permeability could still increase by a mechanism independent of MMP-9. Treatment of cultured mouse microvascular endothelial cells with 30 microM Hcy resulted in significantly greater F-actin formation than in control cells without Hcy. Treatment with a broad-range MMP inhibitor (GM-6001; 1 microM) ameliorated Hcy-induced F-actin formation. These data suggest that Hcy increases microvascular permeability, in part, through MMP-9 activation."


Research confirms that homocysteine is elevated in patients with diabetes and that it interferes with normal wound healing. Here is an excerpt from my book on this.


"By interfering with nitric oxide (NO), homocysteine can prevent wounds from healing normally. The study entitled “Homocysteine--a stealth mediator of impaired wound healing: a preliminary study” states, “Ongoing experimental and clinical wound healing studies have now clearly established NO as a critical mediator of normal tissue repair. Angiogenesis, granulation tissue formation, epidermal migration, collagen deposition, and microvascular homeostasis are significant vulnerary processes, critical to normal wound repair, that are regulated by NO production and bioactivity…Homocysteine antagonizes NO production via multiple pathways…”(Boykin, 2006)."

Here is some information on the involvement of homocysteine in diabetes.

In the following study published in the Annals of Internal Medicine the researchers concluded that homocysteine was a strong and independent risk factor for coronary heart disease (CHD) events in patients with type 2 diabetes. Approximately 80% of people with diabetes die of cardiovascular disease.


Elevated plasma homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus.
Soinio, M., J. Marniemi, M. Laakso, S. Lehto, T. Rönnemaa. 2004. Ann Intern Med. 140(2):94-100.

“…In this large cohort of patients with type 2 diabetes, plasma homo cysteine level was a strong and independent risk factor for CHD events.”


In the following study of 65 patients with type 2 diabetes, elevated levels of homocysteine were found to be independently associated with the prevalence of peripheral neuropathy. The authors suggested that this association could be explained either by direct cytotoxic effects on nerve function, or by small vessel occlusions caused by endothelial damage. This results in a loss of blood supply to nerve fibers, a pathogenetic mechanism of peripheral neuropathy.


Relation between homocysteinaemia and diabetic neuropathy in patients with type 2 diabetes mellitus.
Ambrosch, A., J. Dierkes, R. Lobmann, W. Kühne, W. König, C. Luley, H. Lehnert. 2001. Diabet Med. 18(3):185-92.

“…Since homocysteine exhibits toxic effects on vascular endothelial cells, the association between homocysteine and the prevalence of neuropathy in type 2 diabetes mellitus was investigated… homocysteine levels…and the frequency of hyperhomocysteinemia were significantly increased in neuropathic patients… The data indicate that homocysteine is independently associated with the prevalence of diabetic neuropathy in a collective of type 2 diabetic patients.”

Homocysteine is also associated with ulceration in type 2 diabetes. The study entitled “Plasma homocysteine levels are associated with ulceration of the foot in patients with type 2 diabetes” concluded that for each micromol increase in plasma homocysteine levels there was a 10% increase in the risk of diabetic foot ulceration (González, 2010).

I take two 100 mg per day (AM & PM) of PYCNOGENOL (pine bark extract) to control my type 2 diabetes.

PYCNOGENOL reduces MMP-9 levels and lowers glucose levels and reduces edema and helps heal diabetic wounds.


Clin Appl Thromb Hemost. 2006 Jul;12(3):318-23.

Diabetic ulcers: microcirculatory improvement and faster healing with pycnogenol.

Belcaro G, Cesarone MR, Errichi BM, Ledda A, Di Renzo A, Stuard S, Dugall M, Pellegrini L, Gizzi G, Rohdewald P, Ippolito E, Ricci A, Cacchio M, Cipollone G, Ruffini I, Fano F, Hosoi M.

Abstract

Diabetic microangiopathy leads to lower limb ulcers that are very slow to heal. Pycnogenol was evaluated on diabetic ulcers in a controlled trial. Ulcer medications were used in 4 groups (30 patients): (1) systemic Pycnogenol and local application; (2) local Pycnogenol only; (3) oral Pycnogenol; and (4) medications only (control group). Ulcerated areas and symptom scores were more reduced with the combined oral and local treatment (P < .05). Oral and local treatment were less effective, but still improved compared with the controls. Combined treatment produced 89% complete healing at 6 weeks versus 84% with local treatment and 85% with oral treatment; healing in controls was 61%. The combined treatment group and oral only group had better microcirculation after the combined treatment. Combined local and systemic application of Pycnogenol may offer a new treatment of diabetic ulcers. Local treatment also speeds ulcer healing.


PMID: 16959685 [PubMed - indexed for MEDLINE]

The pine bark extract also helps prevent the vision loss/(maybe blindness) from diabetic retinopathy. Pine bark extract improves microcirculation in capilitaries and prevents microclots from blocking them(retinopathy).

jackD


J Ocul Pharmacol Ther. 2009 Dec;25(6):537-40. doi: 10.1089/jop.2009.0023.

Pycnogenol improves microcirculation, retinal edema, and visual acuity in early diabetic retinopathy.

Steigerwalt R, Belcaro G, Cesarone MR, Di Renzo A, Grossi MG, Ricci A, Dugall M, Cacchio M, Schönlau F.

Abstract

PURPOSE:

The growing numbers of diabetes cases in the developed world are followed by increasing numbers of people diagnosed with diabetic complications. Diabetic microangiopathies in the eye lead to the development of retinopathy involving gradual loss of vision. Previous studies with Pycnogenol showed effectiveness for stopping progression of preproliferative stages of retinopathy. The aim of our study was to show protective effects of Pycnogenol in early stages of retinopathy, characterized by mild to moderate retinal edema in the absence of hemorrhages or hard exudates in the macula center.

METHODS:

Following treatment with Pycnogenol (24 patients) for 3 months, retinal edema score (dilated ophthalmology) and retinal thickness (high resolution ultrasound) showed statistically significant improvement as compared to the placebo group (22 patients), which showed negligible changes to baseline. Laser Doppler flow velocity measurements at the central retinal artery showed a statistically significant increase from 34 to 44 cm/s in the Pycnogenol group as compared to marginal effects in the control group.

RESULTS:

The major positive observation of this study is the visual improvement, which was subjectively perceived by 18 out of 24 patients in the Pycnogenol group. Testing of visual acuity using the Snellen chart showed a significant improvement from baseline 14/20 to 17/20 already, after 2 months treatment, whereas no change was found in the control group.

CONCLUSIONS:

Pycnogenol taken at this early stage of retinopathy may enhance retinal blood circulation accompanied by regression of edema, which favorably improves vision of patients.


PMID: 19916788 [PubMed - indexed for MEDLINE]


Phytother Res. 2001 May;15(3):219-23.
Treatment of vascular retinopathies with Pycnogenol.
Spadea L, Balestrazzi E.

Abstract

The aim of our study was to investigate the effects of Pycnogenol on the progression of diabetic retinopathy and other vascular retinal disorders. The study consisted of a double-blind phase in which 20 patients were recruited and randomly treated with placebo or Pycnogenol (50 mg x 3/day for 2 months) and an open phase in which another 20 patients were treated with Pycnogenol at the same dose schedule. In total, 40 patients with diabetes, atherosclerosis and other vascular diseases involving the retina were enrolled; 30 of them were treated with Pycnogenol and 10 with placebo. The results demonstrated a beneficial effect of Pycnogenol on the progression of retinopathy. Without any treatment (placebo) the retinopathy progressively worsened during the trial and the visual acuity significantly decreased; on the contrary, the Pycnogenol-treated patients showed no deterioration of retinal function and a significant recovery of visual acuity was also obtained. The fluorangiography showed an improvement of retinal vascularization and a reduced endothelial permeability and leakage in the Pycnogenol, but not in the placebo-treated, patients. The ophthalmoscopy and the electroretinogram (ERG) also confirmed the beneficial effects of Pycnogenol. The mechanism of action of Pycnogenol may be related to its free radical (FR) scavenging, anti-inflammatory and capillary protective activities. It has been suggested that Pycnogenol may bind to the blood vessel wall proteins and mucopolysaccharides and produce a capillary 'sealing' effect, leading to a reduced capillary permeability and oedema formation.

Copyright 2001 John Wiley & Sons, Ltd.


PMID: 11351356 [PubMed - indexed for MEDLINE]


Phytother Res. 2013 Jun 15. doi: 10.1002/ptr.5019. [Epub ahead of print]

Pycnogenol® in Chronic Venous Insufficiency and Related Venous Disorders.
Gulati OP.

Abstract

The present review provides an update of the biological profile of Pycnogenol in the light of its use in the treatment of chronic venous insufficiency (CVI) and related venous disorders such as deep vein thrombosis (DVT), post-thrombotic syndrome, long haul air-travel-related leg oedema, venous ulcers and acute haemorrhoids. Pycnogenol is a French maritime pine bark extract produced from the outer bark of Pinus pinaster Ait. subsp. atlantica. Its strong antioxidant, anti-inflammatory and vasodilator activities, antithrombotic effects and collagen stabilizing properties make it uniquely able to target the multi facet pathophysiology of CVI and related venous disorders. Clinical studies have shown that it can reduce oedema of the legs in CVI, reduce the incidence of deep venous thrombosis during long haul flights and enhance the healing of venous ulcers and haemorrhoidal episodes by topical application and/or oral administration. This review highlights clinical research findings on the safety, compliance and efficacy of Pycnogenol, including its use in combination products. Copyright © 2013 John Wiley & Sons, Ltd.

Copyright © 2013 John Wiley & Sons, Ltd.


PMID: 23775628 [PubMed - as supplied by publisher]


Phytother Res. 2010 Aug;24(8):1242-9. doi: 10.1002/ptr.3193.

Effect of pycnogenol on glucose transport in mature 3T3-L1 adipocytes.

Lee HH, Kim KJ, Lee OH, Lee BY

Abstract

Pycnogenol, a procyanidins-enriched extract of Pinus maritima bark, possesses antidiabetic properties, which improves the altered parameters of glucose metabolism that are associated with type 2 diabetes mellitus (T2DM). Since the insulin-stimulated antidiabetic activities of natural bioactive compounds are mediated by GLUT4 via the phosphatidylinositol-3-kinase (PI3K) and/or p38 mitogen activated protein kinase (p38-MAPK) pathway, the effects of pycnogenol were examined on the molecular mechanism of glucose uptake by the glucose transport system. 3T3-L1 adipocytes were treated with various concentrations of pycnogenol, and glucose uptake was examined using a non-radioisotope enzymatic assay and by molecular events associated with the glucose transport system using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results show that pycnogenol increased glucose uptake in fully differentiated 3T3-L1 adipocytes and increased the relative abundance of both GLUT4 and Akt mRNAs through the PI3K pathway in a dose dependent manner. Furthermore, pycnogenol restored the PI3K antagonist-induced inhibition of glucose uptake in the presence of wartmannin, an inhibitor of the PI3K. Overall, these results indicate that pycnogenol may stimulate glucose uptake via the PI3K dependent tyrosine kinase pathways involving Akt. Further the results suggest that pycnogenol might be useful in maintaining blood glucose control.

Copyright (c) 2010 John Wiley & Sons, Ltd.


PMID: 20658573 [PubMed - indexed for MEDLINE]

On a slightly more personal note..

I take a blood pressure drug NIFEDIPIONE which is a calcium channel blocker. This darn drug causes EDEMA in the feet/legs. This is not good if you have diabetes.

I was very pleased to find that Pycnogenol can control this. See abstract below...

jackD



Clin Appl Thromb Hemost. 2006 Oct;12(4):440-4.

Control of edema in hypertensive subjects treated with calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitors with Pycnogenol.

Belcaro G, Cesarone MR, Ricci A, Cornelli U, Rodhewald P, Ledda A, Di Renzo A, Stuard S, Cacchio M, Vinciguerra G, Gizzi G, Pellegrini L, Dugall M, Fano F.

Abstract

The presence of edema in different phases and stages of essential hypertension may be due to antihypertensive treatment. Some drugs may cause edema by inducing vasodilatation, increasing the capillary exchange surface and capillary filtration. Pycnogenol has an important anti-edema effect in diabetic microangiopathy and chronic venous insufficiency. This 8-week study evaluated capillary filtration in 2 comparable treatment groups with hypertension treated with a calcium antagonist (nifedipine) or angiotensin-converting enzyme inhibitor to define its efficacy in preventing edema caused by antihypertensives. A significant decrease in filtration was observed in the Pycnogenol groups. Pycnogenol controls this type of edema, it helps to prevent and limit long-term damage in the microcirculation in hypertensive patients, and allows the dose of anti-hypertensive drugs to be reduced in most patients.


PMID: 17000888 [PubMed - indexed for MEDLINE]


It also appears a second blood pressure drug I take an ACE inhibitor also may cause unwanted edema.

It appears that when MS is in an active state the ACE stuff is elevated. see below abstract.

jackD

p.s. This elevated ACE is also a problem because some Nueros try to use elevated ACE to identify LUPUS which has a constant ACE elevation.


Mult Scler. 2009 Feb;15(2):262-5. doi: 10.1177/1352458508097923. Epub 2009 Jan 9.

Angiotensin-converting enzyme (ACE) and ACE2 levels in the cerebrospinal fluid of patients with multiple sclerosis.

Kawajiri M, Mogi M, Higaki N, Matsuoka T, Ohyagi Y, Tsukuda K, Kohara K, Horiuchi M, Miki T, Kira JI.

Abstract

BACKGROUND:

We reported a reduction in the levels of angiotensin II in cerebrospinal fluid (CSF) from patients with multiple sclerosis (MS).

OBJECTIVE AND METHODS:

To clarify the mechanism underlying this reduction, we assayed angiotensin-converting enzyme (ACE) and ACE2 concentrations along with angiotensin II concentrations in CSF samples from 20 patients with MS and 17 controls with non-neurological diseases.

RESULTS:

ACE levels were significantly elevated in patients with MS compared with controls (48.42 +/- 4.84 vs 44.71 +/- 3.9 pg/mL), whereas ACE2 levels were significantly reduced (2.56 +/- 0.26 vs 2.78 +/- 0.24 pg/mL), acting toward a normalization of angiotensin II levels.

CONCLUSION:

These results further indicate an alteration of the intrathecal renin-angiotensin system in patients with MS.

PMID: 19136547 [PubMed - indexed for MEDLINE]


These ACE inhibitor drugs may have a positive effect by lowering harmful MS destructive activity.






Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14948-53. doi: 10.1073/pnas.0903958106. Epub 2009 Aug 19.

Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.

Platten M, Youssef S, Hur EM, Ho PP, Han MH, Lanz TV, Phillips LK, Goldstein MJ, Bhat R, Raine CS, Sobel RA, Steinman L.



Author information

Abstract

The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway.

Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE.

Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.


PMID: 19706421 [PubMed - indexed for MEDLINE] PMCID: PMC2736463