ACE2 activation alleviates sepsis-induced cardiomyopathy by promoting MasR-Sirt1-mediated mitochondrial biogenesis

Arch Biochem Biophys. 2024 Feb:752:109855. doi: 10.1016/j.abb.2023.109855. Epub 2023 Dec 13.

Abstract

Sepsis-induced cardiomyopathy (SIC), caused by a dysregulated host response to infection, is a major contributor to high mortality. Angiotensin-converting enzyme 2 (ACE2), a crucial component of the renin-angiotensin system (RAS), has protective effects against several cardiovascular diseases, such as myocardial infarction and heart failure. However, the role of ACE2 in the pathogenesis of SIC and underlying mechanisms remain unknown. The present study was designed to examine the effects of ACE2 activation or inhibition on SIC in C57BL/6 mice. The ACE2 activator diminazene aceturate (DIZE) and ACE2 inhibitor MLN-4760 were applied for treatment. Myocardial function, inflammatory response, oxidative stress, apoptosis and mitochondrial biogenesis were investigated. Major assays were echocardiography, H&E staining, immunofluorescence staining, DHE staining, TUNEL staining, Western blot, qPCR analysis, ELISA and corresponding kits. We confirmed that ACE2 was markedly downregulated in septic heart tissues. Pharmacological activation of ACE2 by DIZE ameliorated cecal ligation puncture (CLP)-induced mortality, cardiac dysfunction, inflammatory response, oxidative stress and the cardiomyocyte apoptosis by promoting MasR-Sirt1-mediated mitochondrial biogenesis. In contrast, SIC was aggravated via inhibiting MasR-Sirt1-mediated mitochondrial biogenesis by the use of ACE2 inhibitor MLN-4760. Consequently, activation of ACE2 may protect against SIC by promoting MasR-Sirt1-mediated mitochondrial biogenesis.

Keywords: ACE2; Cecal ligation puncture; MasR-Sirt1; Mitochondrial biogenesis; Sepsis-induced cardiomyopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme 2
  • Animals
  • Cardiomyopathies* / drug therapy
  • Cardiomyopathies* / etiology
  • Mice
  • Mice, Inbred C57BL
  • Organelle Biogenesis
  • Peptidyl-Dipeptidase A
  • Sepsis* / complications
  • Sepsis* / drug therapy
  • Sirtuin 1

Substances

  • Angiotensin-Converting Enzyme 2
  • Peptidyl-Dipeptidase A
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Mas1 protein, mouse
  • Ace2 protein, mouse