Mechanisms of Cardiovascular Remodeling in Hyperhomocysteinemia

Abstract

In hypertension, an increase in arterial wall thickness and loss of elasticity over time result in an increase in pulse wave velocity, a direct measure of arterial stiffness. This change is reflected in gradual fragmentation and loss of elastin fibers and accumulation of stiffer collagen fibers in the media that occurs independently of atherosclerosis. Similar results are seen with an elevated level of homocysteine (Hcy), known as hyperhomocysteinemia (HHcy), which increases vascular thickness, elastin fragmentation, and arterial blood pressure. Studies from our laboratory have demonstrated a decrease in elasticity and an increase in pulse wave velocity in HHcy cystathionine β synthase heterozygote knockout (CBS(-/+)) mice. Nitric oxide (NO) is a potential regulator of matrix metalloproteinase (MMP) activity in MMP-NO-TIMP (tissue inhibitor of metalloproteinase) inhibitory tertiary complex. We have demonstrated the contribution of the NO synthase (NOS) isoforms, endothelial NOS and inducible NOS, in the activation of latent MMP. The differential production of NO contributes to oxidative stress and increased oxidative/nitrative activation of MMP resulting in vascular remodeling in response to HHcy. The contribution of the NOS isoforms, endothelial and inducible in the collagen/elastin switch, has been demonstrated. We have showed that an increase in inducible NOS activity is a key contributor to HHcy-mediated collagen/elastin switch and resulting decline in aortic compliance. In addition, increased levels of Hcy compete and suppress the γ-amino butyric acid-receptor, N-methyl-d-aspartate-receptor, and peroxisome proliferator-activated receptor. The HHcy causes oxidative stress by generating nitrotyrosine, activating the latent MMPs and decreasing the endothelial NO concentration. The HHcy causes elastinolysis and decrease elastic complicance of the vessel wall. The treatment with γ-amino butyric acid-receptor agonist (muscimol), N-methyl-d-aspartate-receptor antagonist (MK-801), and peroxisome proliferator-activated receptor agonists (ciprofibrate and ciglitazone) mitigates the cardiovascular dysfunction in HHcy [corrected].

The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants

“…It is worth reminding that the gaseous NO substrate may work in concert or antagonistically [66,83] to fine-tuning the helpful properties exerted by H 2 S on body tissues. Preliminary studies suggest for instance that NO operates, in combination with H 2 S, as a potential modulator of endothelial remodeling since NO-synthase isoforms contribute to the activation of metalloproteinases involved in the regulation of the collagen/elastin balance defining vascular elastance [83,120].…”

Vascular protective effects of Astragalus membranaceus and its main constituents in rats with chronic hyperhomocysteinemia

“…Cardiovascular disease, which is characterized by dysfunctional conditions of the heart, arteries and veins, remains the most common cause of morbidity and mortality and is a serious threat to human health (1). Age, gender, cigarette smoking, physical inactivity, high blood pressure and serum cholesterol, elevated serum glucose, obesity and family history have been identified as classic risk factors for the development of cardiovascular disease (2).…”

“…Age, gender, cigarette smoking, physical inactivity, high blood pressure and serum cholesterol, elevated serum glucose, obesity and family history have been identified as classic risk factors for the development of cardiovascular disease (2). However, even when all these risk factors are considered, they only explain approximately one-half to two-thirds of the occurrence of cardiovascular disease (1). It appears that additional crucial risk factors remain to be identified.…”

“…Clinical and animal studies have identified that hyperhomocysteinemia (HHcy) may be important in the damage of the vascular structure and function (5)(6)(7). Although a unifying hypothesis has not been established thus far, stress, endothelial dysfunction and vascular remodeling are considered as the primary pathological mechanisms underlying vascular diseases following chronic exposure to Hcy (1). However, in a review of several randomized controlled trials, it was shown that Hcy-lowering interventions were not able to prevent cardiovascular events (8).…”

Organotypic tissue culture investigation of homocysteine thiolactone cardiotoxic effect

“…Cardiac remodeling, which is characterized by accumulation of interstitial and perivascular collagen, was detected in hyperhomocysteinemic animals (2). The data about mechanisms of cardiac remodeling upon homocysteine action are controversial (11,13).…”