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  • Title: Caveolin and β1-integrin coordinate angiotensinogen expression in cardiac myocytes.
    Author: Lal H, Verma SK, Feng H, Golden HB, Gerilechaogetu F, Nizamutdinov D, Foster DM, Glaser SS, Dostal DE.
    Journal: Int J Cardiol; 2013 Sep 20; 168(1):436-45. PubMed ID: 23058350.
    Abstract:
    BACKGROUND: The cardiac renin-angiotensin system (RAS) has been implicated in mediating myocyte hypertrophy and remodeling, although the biochemical mechanisms responsible for regulating the local RAS are poorly understood. Caveolin-1 (Cav-1)/Cav-3 double-knockout mice display cardiac hypertrophy, and in vitro disruption of lipid rafts/caveolae using methyl-β-cyclodextrin (MβCD) abolishes cardiac protection. METHODS: In this study, neonatal rat ventricular myocytes (NRVM) were used to determine whether lipid rafts/caveolae may be involved in the regulation of angiotensinogen (Ao) gene expression, a substrate of the RAS system. RESULTS: Treatment with MβCD caused a time-dependent upregulation of Ao gene expression, which was associated with differential regulation of mitogen-activated protein (MAP) kinases ERK1/2, p38 and JNK phosphorylation. JNK was highly phosphorylated shortly after MβCD treatment (2-30 min), whereas marked activation of ERK1/2 and p38 occurred much later (2-4h). β1D-Integrin was required for MβCD-induced activation of the MAP kinases. Pharmacologic inhibition of ERK1/2 and JNK enhanced MβCD-induced Ao gene expression, whereas p38 blockade inhibited this response. Adenovirus-mediated expression of wild-type p38α enhanced MβCD-induced Ao gene expression; conversely expression of dominant negative p38α blocked the stimulatory effects of MβCD. Expression of Cav-3 siRNA stimulated Ao gene expression, whereas overexpression of Cav-3 was inhibitory. Cav-1 and Cav-3 expression levels were found to be positively regulated by p38, but unaffected by ERK1/2 and JNK. CONCLUSION: Collectively, these studies indicate that lipid rafts/caveolae couple to Ao gene expression through a mechanism that involves β1-integrin and the differential actions of MAP kinase family members.
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