Inhibition of the MEK1 and ERK pathway by amlodipine induces vascular smooth muscle cell differentiation in hypertension

Abstract

Phenotypic modulation of smooth muscle cells (SMCs) is critical in the progression of atherosclerosis. Recent clinical trials have shown that the long-acting calcium antagonist amlodipine has an antiatherogenic property. The molecular mechanisms of this antiathelogenic property of amlodipine, however, remain unknown. We examined the molecular mechanisms behind the phenotypic modulation of aortic SMCs by amlodipine in stroke-prone spontaneously hypertensive rats (SHRSP). Male Wister-Kyoto rats (WKY) and SHRSPs were randomized and treated with a vehicle, amlodipine (5 mg/kg/day), or enalapril (10 mg/kg/day). Both drugs were significantly and equally effective at reducing systolic blood pressure, aortic morphology and collagen deposition in comparison to vehicle-treated SHRSP aortas. In the vehicle SHRSP aortas, contractile-type SM myosin heavy chain (MHC) SM2 was significantly lower, whereas synthetic-type MHC NMHC-B was significantly higher compared with those in the vehicle WKY aorta. Compared to the vehicle SHRSP group, significantly and to the same extent, both drugs reduced NMHC-B and increased SM2, indicating that both drugs induce the phenotype of SMCs in SHRSP aortas toward the differentiated state. In the vehicle SHRSP group, MKK6, p38MAPK, MEK1 and p-42/44 ERK were significantly increased compared with the vehicle WKY group. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, amlodipine significantly lowered MEK1 (23%) and p-42/44 ERK (20%) compared with enalapril, reducing MEK1 and p-42/44 ERK to the same levels as in the vehicle WKY group. In contrast, p-Akt and eNOS were significantly lower in the vehicle SHRSP group than in the vehicle WKY group. The two drugs significantly increased p-Akt and eNOS compared with the vehicle SHRSP group. Furthermore, enalapril was more effective than amlodipine at increasing p-Akt and eNOS in SHRSP aortas. Thus, amlodipine inhibited SMC dedifferentiation through the inhibition of the MEK1 and ERK pathway more effectively than did enalapril in SHRSP aortas, suggesting that the MEK1 and ERK pathways might be crucial determinants for the antiatherogenic property of amlodipine in hypertension.