Grant: CIHR Fellowship

Compelling evidence supports the concept that combination aldosterone and angiotensin II (Ang II) receptor blockade may be therapeutically beneficial in ameliorating vascular injury in cardiovascular disease. Ang II is the principal vasoactive mediator of the renin-angiotensin-aldosterone system (RAAS), which has many actions including vasoconstriction, aldosterone release, inflammation and oxidative stress. Aldosterone, originally described as an important regulator of blood pressure and electrolytic balance, is now considered a key player in cellular processes underlying cardiovascular hypertrophy and fibrosis. Recent data have suggested complex interactions between Ang II and aldosterone in vivo. However cellular mechanisms and signaling pathways implicated in the cross-talk between Ang II and aldosterone are currently subjects of investigation. We identified a novel nongenomic signaling pathway for aldosterone, involving c-Src-dependent activation of p38MAPK and NAD(P)H oxidase-mediated generation of superoxide anion in VSMCs (Hypertension. 2005;46:1032). We also highlighted the importance of c-Src in the molecular and cellular processes underlying vascular activation of MAPK-dependent growth signaling and oxidative stress by Ang II (Hypertension. 2002;39:479). However, evidence for a direct role of c-Src in Ang II and aldosterone synergistic effects in VSMCs is still lacking. We showed that there is differential cross-talk between Ang II and aldosterone involving c-Src-dependent and independent signaling pathways (Arterioscler Thromb Vasc Biol. 2008;28:1511, Hypertension (in press). In VSMC, Ang II and aldosterone acting together through c-Src, leads to ROS formation and RhoA pathway activation. What remains unclear is how c-Src regulates cross-talk between Ang II and aldosterone and whether c-Src-mediated aldosterone and Ang II synergism contributes to the development of hypertension and associated cardiovascular damage.