Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis
Background—Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H2S) in the cardiovascular system. The deficiency of CSE in mice leads to decreased endogenous H2S level, age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H2S in atherosclerosis development.
Methods and Results—Six-week old CSE gene knockout (KO) and wild-type (WT) mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation and adhesion molecule expression were then analysed. CSE-KO mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein (LDL) cholesterol, hyperhomocystenemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-KO mice with NaHS, but not N-acetyl cysteine or ezetimibe, inhibited the accelerated atherosclerosis development. Double knockout of CSE and apolipoprotein E (apoE) gene expression in mice exacerbated atherosclerosis development more than that in the mice with only apoE or CSE knockout.
Conclusions—Endogenously synthesized H2S protects vascular tissues from atherogenic damage by reducing vessel intimal proliferation and inhibiting adhesion molecule expression. Decreased endogenous H2S production predisposes the animals to vascular remodelling and early development of atherosclerosis. The CSE/H2S pathway is an important therapeutic target for protection against atherosclerosis.
- Received February 22, 2013.
- Revision received April 25, 2013.
- Accepted April 29, 2013.