[The role of endogenous CO in the regulation of endothelin-induced VSMC proliferation and MAPK activity].

Heme oxygenase (HO) is a rate-limiting enzyme of heme degradation, which converts the cellular heme to bilirubin and carbon monoxide (CO). Recently it is suggested that endogenous CO plays an important role in regulating vascular tone under both physiological and pathological conditions, but it is not clear whether endogenous HO/CO system regulates vascular smooth muscle cell (VSMC) proliferation. In the present study, VMSC 3H-TdR incorporation, mitogen-activated protein kinase (MAPK) activity, HO activity and CO release were determined to study the role of endogenous HO/CO system in regulating the VSMC proliferation induced by endothelin-1 (ET-1) in a cultured system. The results showed that ET-1 increased VSMC 3H-TdR incorporation, MAPK activity, HO activity, and CO release were up-regulated. Pretreatment of HO inhibitor, zinc protoporphyrin-9 (ZnPP-9), increased the ET-1-induced VSMC 3H-TdR incorporation and MAPK activity by 31.8% and 36.6% (P < 0.01, respectively), whereas pretreatment of heme-L-lysinate (HLL), a HO substrate, inhibited these activities. This study demonstrated that up-regulation of VSMC endogenous HO represents a cellular protective response to stress or injury. Inhibition of HO may enhance VSMC proliferation induced by ET-1 in vitro, suggesting that endogenous HO/CO system may be directly involved in the regulation of VSMC proliferation through MAPK signaling pathway.