Cystathionine gamma-lyase deficiency and overproliferation of smooth muscle cells

Cystathionine gamma-lyase (CSE)-derived H(2)S plays an important role in regulating cell growth. Lack of CSE expression results in development of hypertension. The current study compared proliferation of smooth muscle cells derived from CSE gene knockout mice (SMCs-KO) with that of wild-type mice (SMCs-WT). Cell proliferation was assessed by bromodeoxyuridine incorporation. Gene expression was analysed by western blotting, real-time PCR, and microarray analysis. Enhanced cell proliferation was detected in SMCs-KO and in the media of the aorta from CSE KO mice. SMCs-KO underwent significantly more apoptosis than SMCs-WT when treated with exogenous H(2)S (100 mu M). CSE KO mice showed much lower level of phosphorylated extracellular signal-regulated kinase (ERK1/2) in mesentery arteries compared with those of WT mice, and exogenous H(2)S induced more phosphorylation of ERK1/2 in SMCs-KO compared with that in SMCs-WT. Decreased p21(Cip/WAF-1) but increased cyclin D1 expression was observed in isolated SMCs and vascular tissues from CSE KO mice, and exogenous H(2)S caused more increase in p21(Cip/WAF-1) expression and more decrease in cyclin D1 expression in SMCs-KO than in SMCs-WT. The transcriptional expression of calcitonin receptor-like, intergrin beta 1, and heparin-binding epidermal growth factor-like growth factor was also significantly increased in the aorta of CSE KO mice. SMCs-KO display an increased proliferation rate in vitro and in vivo, and these cells are more susceptible to apoptosis induced by exogenous H(2)S at physiologically relevant concentrations. These cellular effects of H(2)S are mediated by phosphorylation of ERK1/2 and altered expression of cyclin D1 and p21(Cip/WAF-1).