The Role Of Putative Nox Inhibitors In Homocysteine-Induced Vascular Dysfunction
Abstract
Excess plasma homocysteine (Hcy; hyperhomocysteinemia, HHcy) remains an independent risk factor for cardiovascular disease (CVD) and treatments remain elusive. The source of Hcy, methionine, is an essential amino acid acquired by ingestion of animal foods. Normal methionine metabolism effectively removes Hcy via recycling back into methionine or excretion via the kidney. However, in aberrant methionine metabolism, Hcy accumulates and causes damage to the vascular system by increasing oxidative stress; the exact mechanism of how this occurs is unknown. Importantly, the B vitamins B6, B9 and B12 are essential to proper methionine/Hcy metabolism and are often found in low levels in patients presenting with HHcy; this has provided a potentially viable treatment strategy in the clinical setting. Disappointingly, clinical trials administering B vitamins to reduce HHcy have been unsuccessful in reducing CVD and treatments continue to be sought. The NADPH oxidase (Nox) family of enzymes are expressed in a broad range of cell types throughout the body and are the primary source of superoxide (Nox1, Nox2) and hydrogen peroxide (Nox4) within the vasculature under both physiological and pathological conditions. Nox1, 2 and 4 are of primary interest in vascular disease, as there is evidence that Hcy can interfere with the proper function of Nox1, 2 and 4 signalling, potentially leading to an over-expression of pro-oxidants. Nox1, 2 and 4 have been implicated in vascular disease…
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