Role of hyperhomocysteinemia in endothelial dysfunction and atherothrombotic disease

Cell Death Differ. 2004 Jul:11 Suppl 1:S56-64. doi: 10.1038/sj.cdd.4401451.

Abstract

Hyperhomocysteinemia (HHcy) is an independent risk factor for cardiovascular disease, including ischemic heart disease, stroke, and peripheral vascular disease. Mutations in the enzymes responsible for homocysteine metabolism, particularly cystathionine beta-synthase (CBS) or 5,10-methylenetetrahydrofolate reductase (MTHFR), result in severe forms of HHcy. Additionally, nutritional deficiencies in B vitamin cofactors required for homocysteine metabolism, including folic acid, vitamin B6 (pyridoxal phosphate), and/or B12 (methylcobalamin), can induce HHcy. Studies using animal models of genetic- and diet-induced HHcy have recently demonstrated a causal relationship between HHcy, endothelial dysfunction, and accelerated atherosclerosis. Dietary enrichment in B vitamins attenuates these adverse effects of HHcy. Although oxidative stress and activation of proinflammatory factors have been proposed to explain the atherogenic effects of HHcy, recent in vitro and in vivo studies demonstrate that HHcy induces endoplasmic reticulum (ER) stress, leading to activation of the unfolded protein response (UPR). This review summarizes the current role of HHcy in endothelial dysfunction and explores the cellular mechanisms, including ER stress, that contribute to atherothrombosis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Arteriosclerosis / etiology*
  • Cardiovascular Diseases / etiology
  • Cell Adhesion / physiology
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum / physiology
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology*
  • Homocysteine / metabolism
  • Homocysteine / physiology
  • Humans
  • Hyperhomocysteinemia / complications*
  • Hyperhomocysteinemia / physiopathology
  • Inflammation / etiology
  • Models, Biological
  • Oxidative Stress / physiology
  • Protein Folding
  • Risk Factors
  • Thrombosis / etiology*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism
  • Transcription Factors / physiology

Substances

  • Phlda1 protein, mouse
  • Transcription Factors
  • Homocysteine