Caveolin and β1-integrin coordinate angiotensinogen expression in cardiac myocytes

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-beta-cyclodextrin (M beta CD) 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 M beta CD 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 M beta CD treatment (2-30 min), whereas marked activation of ERK1/2 and p38 occurred much later (2-4 h). beta(1D)-Integrin was required for M beta CD-induced activation of the MAP kinases. Pharmacologic inhibition of ERK1/2 and JNK enhanced M beta CD-induced Ao gene expression, whereas p38 blockade inhibited this response. Adenovirus-mediated expression of wild-type p38 alpha enhanced M beta CD-induced Ao gene expression; conversely expression of dominant negative p38 alpha blocked the stimulatory effects of M beta CD. 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 beta(1)-integrin and the differential actions of MAP kinase family members. Published by Elsevier Ireland Ltd.