Angiotensin-converting enzyme 2 inhibits high-mobility group box 1 and attenuates cardiac dysfunction...

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Inflammation Research

Background:

• High-mobility group box 1 (HMGB1) exacerbates inflammation after ischemic injury, correlating with poor outcomes in myocardial infarction (MI).
• Angiotensin-converting enzyme 2 (ACE2) is a vasoprotective enzyme within the renin-angiotensin system (RAS) that benefits cardiovascular health.
• The interplay between HMGB1 and ACE2 in the context of MI remains uninvestigated.

Purpose of the Study:

• To investigate the hypothesis that elevated ACE2 expression confers cardioprotection against MI by suppressing HMGB1 and inflammation.
• To explore the therapeutic potential of ACE2 in mitigating ischemic heart damage.

Main Methods:

• Utilized ACE2 knock-in (KI) mice and wild-type (WT) controls subjected to myocardial infarction (MI) induction via coronary artery ligation.
• Assessed cardiac function post-MI using echocardiography and Millar catheterization.
• Analyzed cardiac tissues for histological changes, apoptosis, macrophage infiltration, and expression of HMGB1, RAS components, and inflammatory cytokines (TNF-α, IL-6).
• Conducted in vitro studies on adult cardiomyocytes to evaluate ACE2 activation effects on hypoxia-induced cell death and HMGB1 upregulation.

Main Results:

• ACE2-KI mice demonstrated significantly preserved cardiac function and reduced infarct size compared to WT-MI mice.
• ACE2 overexpression markedly decreased MI-induced apoptosis, macrophage infiltration, and levels of HMGB1, TNF-α, and IL-6.
• In vitro, ACE2 activation protected cardiomyocytes from hypoxia-induced cell death and HMGB1 upregulation.

Conclusions:

• Overexpression of ACE2 provides significant cardioprotection against myocardial infarction in mice.
• The protective mechanism involves the downregulation of HMGB1 and associated proinflammatory cytokines.
• ACE2 activation presents a promising therapeutic strategy for treating ischemic heart disease.