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Endothelial α1-adrenergic receptor activation improves cardiac function in septic mice via PKC-ERK/p38MAPK signaling
Tian Tian1, Qing Yu1, Duomeng Yang1
1Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou 510632, China.
Insights
Activating alpha 1 adrenergic receptors (α1-AR) on heart endothelial cells protects against sepsis-induced cardiomyopathy. This approach inhibits endothelial injury via specific signaling pathways, improving cardiac function and survival in septic mice.
Area of Science:
- Cardiovascular Biology
- Sepsis Pathophysiology
- Adrenergic Receptor Signaling
Background:
- Sepsis frequently causes cardiomyopathy, impacting patient outcomes.
- Previous research indicated cardiomyocyte α1-AR activation mitigates sepsis-induced myocardial dysfunction.
- The specific role of endothelial α1-AR in septic cardiomyopathy remained unelucidated.
Purpose of the Study:
- To investigate the function of cardiac endothelial α1-AR in sepsis-induced cardiomyopathy.
- To determine the molecular mechanisms by which endothelial α1-AR activation influences septic cardiac dysfunction.
Main Methods:
- Identified α1-AR expression in mouse and human cardiac endothelial cells.
- Administered phenylephrine (PE) to activate α1-AR in septic mice.
- Utilized molecular assays to assess endothelial cell markers, signaling pathway activation (PKC, ERK1/2, p38MAPK), and p65 nuclear translocation in LPS-treated cells.
- Employed specific inhibitors for PKC, α1-AR, and ERK1/2 (U0126).
Main Results:
- Activation of cardiac endothelial α1-AR with PE improved cardiac function and survival in septic mice.
- PE treatment reduced endothelial injury markers (ICAM-1, VCAM-1, iNOS, E-selectin) and p-p38MAPK expression.
- PE promoted PKC and ERK1/2 phosphorylation, effects blocked by PKC inhibitor or α1-AR antagonist.
- PE suppressed p65 nuclear translocation independently of PKC inhibition.
- ERK1/2 inhibition reversed PE's effects on p38MAPK phosphorylation.
Conclusions:
- Cardiac endothelial α1-AR activation prevents sepsis-induced myocardial dysfunction in mice.
- This protection is mediated by inhibiting endothelial injury through a PKC-ERK/p38MAPK signaling pathway.
- A PKC-independent inhibition of p65 nuclear translocation also contributes to the protective effect.
- Targeting cardiac endothelial α1-AR represents a potential therapeutic strategy for septic cardiomyopathy by preventing endothelial cell injury.
Abstract:
Cardiomyopathy is particularly common in septic patients. Our previous studies have shown that activation of the alpha 1 adrenergic receptor (α1-AR) on cardiomyocytes inhibits sepsis-induced myocardial dysfunction. However, the role of cardiac endothelial α1-AR in septic cardiomyopathy has not been determined. Here, we identified α1-AR expression in mouse and human endothelial cells and showed that activation of α1-AR with phenylephrine (PE) improved cardiac function and survival by preventing cardiac endothelial injury in septic mice. Mechanistically, activating α1-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 α1-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 α1-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 α1-AR activation.
