Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.17 (MMP-3)
 3,419 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.
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PMID:Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger's disease. 1700 Aug 87

Remodeling and myocardial matrix metabolism contributes to cardiac endothelium-myocyte (perivascular fibrosis), myocyte-myocyte (interstitial fibrosis), and mitochondrion-myocyte (fusion and fission) coupling. Matrix metalloproteinases (MMPs), and tissue inhibitor of metalloproteinases (TIMPs) play differential roles in different tissues and diseases. For example, although present in the heart, MMP-3 is known as stromelysin (i.e., stromal tissue enzyme). Interestingly, TIMP-3 causes apoptosis. Exercise and nutrition are synergistic in the mitigation of diseases: exercise releases exosomes containing miRNAs. Nutrition/vitamins B6 and B12 regulate the metabolism of homocysteine (an epigenetic byproduct of DNA/RNA/protein methylation). Thus, epigenetic silencing is an important therapeutic target. The statistical analysis of cohorts may be less indicative for the treatment of a disease, particularly if the 2 twins are different in terms of responding to the medicine for the same disease, therefore, personalized medicine is the future of therapy.
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PMID:Exercise and nutrition in myocardial matrix metabolism, remodeling, regeneration, epigenetics, microcirculation, and muscle. 2495 92