Vascular complications of cystathionine β-synthase deficiency: future directions for homocysteine-to-hydrogen sulfide research
- 1 January 2011
- journal article
- review article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 300 (1), H13-H26
- https://doi.org/10.1152/ajpheart.00598.2010
Abstract
Homocysteine (Hcy), a cardiovascular and neurovascular disease risk factor, is converted to hydrogen sulfide (H2S) through the transsulfuration pathway. H2S has attracted considerable attention in recent years for many positive effects on vascular health and homeostasis. Cystathionine β-synthase (CBS) is the first, and rate-limiting, enzyme in the transsulfuration pathway. Mutations in the CBS gene decrease enzymatic activity, which increases the plasma Hcy concentration, a condition called hyperhomocysteinemia (HHcy). Animal models of CBS deficiency have provided invaluable insights into the pathological effects of transsulfuration impairment and of both mild and severe HHcy. However, studies have also highlighted the complexity of HHcy and the need to explore the specific details of Hcy metabolism in addition to Hcy levels per se. There has been a relative paucity of work addressing the dysfunctional H2S production in CBS deficiency that may contribute to, or even create, HHcy-associated pathologies. Experiments using CBS knockout mice, both homozygous (−/−) and heterozygous (+/−), have provided 15 years of new knowledge and are the focus of this review. These murine models present the opportunity to study a specific mechanism for HHcy that matches one of the etiologies in many human patients. Therefore, the goal of this review was to integrate and highlight the critical information gained thus far from models of CBS deficiency and draw attention to critical gaps in knowledge, with particular emphasis on the modulation of H2S metabolism. We include findings from human and animal studies to identify important opportunities for future investigation that should be aimed at generating new basic and clinical understanding of the role of CBS and transsulfuration in cardiovascular and neurovascular disease.Keywords
This publication has 185 references indexed in Scilit:
- Acceleration of brain amyloidosis in an Alzheimer’s disease mouse model by a folate, vitamin B6 and B12-deficient dietExperimental Gerontology, 2010
- Hydrogen sulfide mitigates matrix metalloproteinase-9 activity and neurovascular permeability in hyperhomocysteinemic miceNeurochemistry International, 2010
- Birth Prevalence of Homocystinuria in Central Europe: Frequency and Pathogenicity of Mutation c.1105C>T (p.R369C) in the Cystathionine Beta-Synthase GeneThe Journal of Pediatrics, 2009
- Nitrotyrosinylation, remodeling and endothelial‐myocyte uncoupling in iNOS, cystathionine beta synthase (CBS) knockouts and iNOS/CBS double knockout miceJournal of Cellular Biochemistry, 2008
- Mortality and Cardiovascular Events in Patients Treated With Homocysteine-Lowering B Vitamins After Coronary AngiographyJAMA, 2008
- GABAA receptor agonist mitigates homocysteine-induced cerebrovascular remodeling in knockout miceBrain Research, 2008
- Hypertension and Cerebrovascular DysfunctionCell Metabolism, 2008
- Effect of Folic Acid and B Vitamins on Risk of Cardiovascular Events and Total Mortality Among Women at High Risk for Cardiovascular DiseaseJAMA, 2008
- Association of Plasma Total Homocysteine Levels With Subclinical Brain InjuryArchives of Neurology, 2008
- The possible role of hydrogen sulfide as a smooth muscle cell proliferation inhibitor in rat cultured cellsHeart and Vessels, 2004