Role of nifedipine and hydrochlorothiazide in MAPK activation and vascular smooth muscle cell proliferation and apoptosis.

Abstract

Once hypertensionis established, increased mechanical stretch stress becomes aleading cause of vascular remodeling. Clinical antihypertension guidelines demonstrate that antihypertension drugs prevent vascular remodeling in hypertensive patients mainly by lowering blood pressure, suggesting an indirect way of reducing the effects of stretch stress (hypertension). Whether these drugs can directly block the effects of the stretch stress on vascular remodeling has not been reported to date. This study was designed to answer this question and explore the underlying mechanisms. Cultured quiescent vascular smooth muscle cells (VSMCs) were stimulated by stretch stress after pretreatment with nifedipine and hydrochlorothiazide. The phosphorylation levels of extracellular signal-regulated kinases (ERKs), c‑Jun NH2-terminal protein kinases (JNKs), and p38 mitogen-activated protein kinase (MAPK) in VSMCs were detected via Western blotting. The treated cells were stained using triple-labeled immunofluorescence with Ki67 antibody and a TUNEL kit in the presence of DAPI for the detection of proliferative, apoptotic, and resting cells. Compared with the negative control, both nifedipine and hydrochlorothiazide had no influence on the phosphorylation of MAPKs and on the proliferation and apoptosis of VSMCs in resting state. Stretch stress could significantly induce increased phosphorylation of MAPKs as well as proliferation and apoptosis of VSMCs. Nifedipine inhibited the effects of stretch stress in adose-dependent manner. Contrary to the effects of nifedipine, hydrochlorothiazide synergistically amplified the effects induced by stretch stress. Nifedipine and hydrochlorothiazide have opposing functions in the increased phosphorylation of MAPK and in the proliferation and apoptosis of VSMCs induced by stretch stress. The former plays a role as an inhibitor, while the latter functions as apromoter.