Endothelial α1-adrenergic receptor activation improves cardiac function in septic mice via PKC-ERK/p38MAPK signaling pathway
Tian Tian, Qing Yu, Duomeng Yang, Xue Zhang, Chanjuan Zhang, Jianling Li, Tao Luo, Keke Zhang, Xiuxiu Lv, Yiyang Wang, Huadong Wang, Hongmei Li
Abstract
• Cardiac endothelial α 1 -AR activation inhibits cardiac dysfunction of septic mice. • Cardiac endothelial α 1 -AR activation inhibits endothelial injuries of septic mice. • The inhibition of endothelial injuries was via PKC-ERK/p38MAPK pathway. Cardiomyopathy is particularly common in septic patients. Our previous studies have shown that activation of the alpha 1 adrenergic receptor (α 1 -AR) on cardiomyocytes inhibits sepsis-induced myocardial dysfunction. However, the role of cardiac endothelial α 1 -AR in septic cardiomyopathy has not been determined. Here, we identified α 1 -AR expression in mouse and human endothelial cells and showed that activation of α 1 -AR with phenylephrine (PE) improved cardiac function and survival by preventing cardiac endothelial injury in septic mice. Mechanistically, activating α 1 -AR with PE decreased the expression of ICAM-1, VCAM-1, iNOS, E-selectin, and p-p38MAPK, while promoting PKC and ERK1/2 phosphorylation in LPS-treated endothelial cells. These effects were abolished by a PKC inhibitor or α 1 -AR antagonist. PE also reduced p65 nuclear translocation, but this suppression is not blocked by PKC inhibition. Treatment with U0126 (a specific ERK1/2 inhibitor) reversed the effects of PE on p38MAPK phosphorylation. Our results demonstrate that cardiac endothelial α 1 -AR activation prevents sepsis-induced myocardial dysfunction in mice by inhibiting the endothelial injury via PKC-ERK/p38MAPK signaling pathway and a PKC-independent inhibition of p65 nuclear translocation. These findings offer a new perspective for septic patients with cardiac dysfunction by inhibiting cardiac endothelial cell injury through α 1 -AR activation.