Angiotensin receptor-neprilysin inhibitor improves coronary collateral perfusion

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

doi:10.3389/fcvm.2022.981333

Angiotensin receptor-neprilysin inhibitor improves coronary collateral perfusion

Front Cardiovasc Med. 2023 Feb 3:9:981333. doi: 10.3389/fcvm.2022.981333. eCollection 2022.

Authors

Kangbo Li^{1

2

3}, Victoria Kratzmann¹, Mengjun Dai^{1

2}, Nora Gatzke¹, Petra Rocic⁴, Peter Bramlage⁵, Olaf Grisk⁶, Lubomir T Lubomirov⁶, Meike Hoffmeister^{7

8}, Martin A Lauxmann⁷, Oliver Ritter^{8

9}, Eva Buschmann¹⁰, Michael Bader^{2

3

11

12}, Anja Bondke Persson², Ivo Buschmann^{1

8}, Philipp Hillmeister^{1

8}

Affiliations

¹ Department for Angiology, Center for Internal Medicine I, Deutsches Angiologie Zentrum Brandenburg - Berlin, University Clinic Brandenburg, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany.
² Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
³ Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
⁴ Department of Physiology and Pharmacology, College of Osteopathic Medicine, Sam Houston State University, Huntsville, TX, United States.
⁵ Institute for Pharmacology and Preventive Medicine, Cloppenburg, Germany.
⁶ Institute of Physiology, Brandenburg Medical School Theodor Fontane, Neuruppin, Germany.
⁷ Institute of Biochemistry, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany.
⁸ Faculty of Health Sciences Brandenburg, Joint Faculty of the Brandenburg University of Technology Cottbus - Senftenberg, The Brandenburg Medical School Theodor Fontane, University of Potsdam, Brandenburg an der Havel, Germany.
⁹ Department for Cardiology, Center for Internal Medicine I, University Clinic Brandenburg, Brandenburg Medical School Theodor Fontane, Brandenburg an der Havel, Germany.
¹⁰ Department of Cardiology, University Clinic Graz, Graz, Austria.
¹¹ German Center for Cardiovascular Research, Partner Site Berlin, Berlin, Germany.
¹² Institute for Biology, University of Lübeck, Lübeck, Germany.

Abstract

Background: We 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.

Methods: A 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.

Results: The 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.

Conclusion: ARNis improve coronary collateral perfusion and exert pro-arteriogenic effects via the bradykinin receptor signaling pathway.

Keywords: angiotensin receptor-neprilysin inhibitor; angiotensin-converting enzyme inhibitor; arteriogenesis; coronary collateral perfusion; heart failure; kallikrein-kinin system; myocardial infarction.

Grants and funding

This work was supported by the Faculty of Health Sciences Brandenburg (Fakultät für Gesundheitswissenschaften Brandenburg, FGW). The open-access publishing was funded by the Brandenburg Medical School Theodor Fontane (Medizinische Hochschule Brandenburg Theodor Fontane, MHB) publication funding supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG).