Molecular Mechanisms of Adiponectin-Induced Attenuation of Mechanical Stretch-Mediated Vascular Remodeling
AuthorGhantous, Crystal M.
Korashy, Hesham M.
MetadataShow full item record
Hypertension induces vascular hypertrophy, which changes blood vessels structurally and functionally, leading to reduced tissue perfusion and further hypertension. It is also associated with dysregulated levels of the circulating adipokines leptin and adiponectin (APN). Leptin is an obesity-associated hormone that promotes vascular smooth muscle cell (VSMC) hypertrophy. APN is a cardioprotective hormone that has been shown to attenuate hypertrophic cardiomyopathy. In this study, we investigated the molecular mechanisms of hypertension-induced VSMC remodeling and the involvement of leptin and APN in this process. To mimic hypertension, the rat portal vein (RPV) was mechanically stretched, and the protective eﬀects of APN on mechanical stretch-induced vascular remodeling and the molecular mechanisms involved were examined by using 10μg/ml APN. Mechanically stretching the RPV signiﬁcantly decreased APN protein expression after 24 hours and APN mRNA expression in a time-dependent manner in VSMCs. The mRNA expression of the APN receptors AdipoR1, AdipoR2, and Tcadherin signiﬁcantly increased after 15 hours of stretch. The ratio of APN/leptin expression in VSMCs signiﬁcantly decreased after 24 hours of mechanical stretch. Stretching the RPV for 3 days increased the weight and [3H]-leucine incorporation signiﬁcantly, whereas APN signiﬁcantly reduced hypertrophy in mechanically stretched vessels. Stretching the RPV for 10 minutes signiﬁcantly decreased phosphorylation of LKB1, AMPK, and eNOS, while APN signiﬁcantly increased p-LKB1, pAMPK, and p-eNOS in stretched vessels. Mechanical stretch signiﬁcantly increased p-ERK1/2 after 10 minutes, whereas APN signiﬁcantly reduced stretch-induced ERK1/2 phosphorylation. Stretching the RPV also signiﬁcantly increased ROS generation after 1 hour, whereas APN signiﬁcantly decreased mechanical stretch-induced ROS production. Exogenous leptin (3.1nM) markedly increased GATA-4 nuclear translocation in VSMCs, whereas APN signiﬁcantly attenuated leptin-induced GATA-4 nuclear translocation. Our results decipher molecular mechanisms of APN-induced attenuation of mechanical stretch-mediated vascular hypertrophy, with the promising potential of ultimately translating this protective hormone into the clinic.