LIPID RAFT AND MAP KINSE INTERACTION PLAY A KEY ROLE IN ANGIOTENSIN II PRECONDITIONING OF THE HEART

Abstract

Previous studies showed that angiotensin II[AngII] could precondition [PC] a heart by modulating MAP kinase signaling. Since lipid raft can modulate MAP kinase signaling, we hypothesized that lipid raft could play a role in AngII PC. A group of rat hearts was treated with Ang II in absence or presence of a NADPH oxidase inhibitor, apocynin or a cell permeable ROS scavenger, N-acetyl-cysteine (NAC). Ang II improved post-ischemic ventricular recovery, reduced myocardial infraction and cardiomyocyte apoptosis Both apocynin and NAC abolished cardioprotection of Ang II PC. In Ang II treated heart, there was decreased association of anti-death signaling components (p38MAPKb, ERK1/2) with caveolin while there was increased association of death signaling components (p38MAPKa, JNK) indicating reduced amount of death signaling components and increased amount of anti-death signaling components were available to the Ang II treated hearts to generate a survival signal. In contrast, in I/R heart, there was an increased association of anti-death signaling components (p38MAPKb, ERK1/2) with caveolin while there was reduced association of death signaling components (p38MAPKa, JNK) indicating increased amount of death signaling components were available to I/R hearts to generate a death signal. When Ang II preconditioned hearts were treated with NAC and apocynin caveolin–MAPK interaction showed similar pattern like I/R heart. The survival signal was further confirmed by increased phosphorylation of AKT and enhanced induction of the expression of Bcl-2 during Ang II precondition and its reversal with I/R, NAC and apocynin treated hearts. These results indicated a unique MAP kinase signaling in Ang II heart involving lipid rafts which generated survival signal by differentially associating MAP kinases with caveolin.