Caveolin and 1-integrin coordinate angiotensinogen expression in cardiac myocytes. Academic Article uri icon

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

published proceedings

  • Int J Cardiol

author list (cited authors)

  • Lal, H., Verma, S. K., Feng, H., Golden, H. B., Gerilechaogetu, F., Nizamutdinov, D., ... Dostal, D. E.

publication date

  • January 1, 2013 11:11 AM