Frontiers in Cardiovascular Medicine (Feb 2023)

Angiotensin receptor-neprilysin inhibitor improves coronary collateral perfusion

  • Kangbo Li,
  • Kangbo Li,
  • Kangbo Li,
  • Victoria Kratzmann,
  • Mengjun Dai,
  • Mengjun Dai,
  • Nora Gatzke,
  • Petra Rocic,
  • Peter Bramlage,
  • Olaf Grisk,
  • Lubomir T. Lubomirov,
  • Meike Hoffmeister,
  • Meike Hoffmeister,
  • Martin A. Lauxmann,
  • Oliver Ritter,
  • Oliver Ritter,
  • Eva Buschmann,
  • Michael Bader,
  • Michael Bader,
  • Michael Bader,
  • Michael Bader,
  • Anja Bondke Persson,
  • Ivo Buschmann,
  • Ivo Buschmann,
  • Philipp Hillmeister,
  • Philipp Hillmeister

DOI
https://doi.org/10.3389/fcvm.2022.981333
Journal volume & issue
Vol. 9

Abstract

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BackgroundWe investigated the pleiotropic effects of an angiotensin receptor-neprilysin inhibitor (ARNi) on collateral-dependent myocardial perfusion in a rat model of coronary arteriogenesis, and performed comprehensive analyses to uncover the underlying molecular mechanisms.MethodsA rat model of coronary arteriogenesis was established by implanting an inflatable occluder on the left anterior descending coronary artery followed by a 7-day repetitive occlusion procedure (ROP). Coronary collateral perfusion was measured by using a myocardial particle infusion technique. The putative ARNi-induced pro-arteriogenic effects were further investigated and compared with an angiotensin-converting enzyme inhibitor (ACEi). Expression of the membrane receptors and key enzymes in the natriuretic peptide system (NPS), renin-angiotensin-aldosterone system (RAAS) and kallikrein-kinin system (KKS) were analyzed by quantitative polymerase chain reaction (qPCR) and immunoblot assay, respectively. Protein levels of pro-arteriogenic cytokines were measured by enzyme-linked immunosorbent assay, and mitochondrial DNA copy number was assessed by qPCR due to their roles in arteriogenesis. Furthermore, murine heart endothelial cells (MHEC5-T) were treated with a neprilysin inhibitor (NEPi) alone, or in combination with bradykinin receptor antagonists. MHEC5-T proliferation was analyzed by colorimetric assay.ResultsThe in vivo study showed that ARNis markedly improved coronary collateral perfusion, regulated the gene expression of KKS, and increased the concentrations of relevant pro-arteriogenic cytokines. The in vitro study demonstrated that NEPis significantly promoted MHEC5-T proliferation, which was diminished by bradykinin receptor antagonists.ConclusionARNis improve coronary collateral perfusion and exert pro-arteriogenic effects via the bradykinin receptor signaling pathway.

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