Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

Bódi, Beáta; Pilz, Patrick M.; Mártha, Lilla; Lang, Miriam; Hamza, Ouafa; Fagyas, Miklós; Szabó, Petra L.; Abraham, Dietmar; Tóth, Attila; Podesser, Bruno K.; Kiss, Attila; Papp, Zoltán

doi:10.3390/ijms222011064

Open AccessArticle

Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

by

Beáta Bódi

^1,†,

Patrick M. Pilz

^2,†

,

Lilla Mártha

¹,

Miriam Lang

²,

Ouafa Hamza

²,

Miklós Fagyas

¹

,

Petra L. Szabó

²

,

Dietmar Abraham

³

,

Attila Tóth

^1,4

,

Bruno K. Podesser

²

,

Attila Kiss

^2,*,†

and

Zoltán Papp

^1,4,*,†

¹

Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary

²

Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria

³

Center for Anatomy and Cell Biology, Medical University Vienna, 1090 Vienna, Austria

⁴

HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to the work.

Int. J. Mol. Sci. 2021, 22(20), 11064; https://doi.org/10.3390/ijms222011064

Submission received: 9 September 2021 / Revised: 8 October 2021 / Accepted: 12 October 2021 / Published: 14 October 2021

(This article belongs to the Special Issue Molecular Mechanisms of Cardioprotection)

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Abstract

Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague–Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 ± 2.1% to 50 ± 1.6%, mean ± SEM, p < 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 ± 4.8% to 55.2 ± 4.1%, p < 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca²⁺-sensitivities of force production (pCa₅₀) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa₅₀, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.

Keywords: repeated remote ischemic conditioning; cardiomyocyte mechanics; signaling

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MDPI and ACS Style

Bódi, B.; Pilz, P.M.; Mártha, L.; Lang, M.; Hamza, O.; Fagyas, M.; Szabó, P.L.; Abraham, D.; Tóth, A.; Podesser, B.K.; et al. Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning. Int. J. Mol. Sci. 2021, 22, 11064. https://doi.org/10.3390/ijms222011064

AMA Style

Bódi B, Pilz PM, Mártha L, Lang M, Hamza O, Fagyas M, Szabó PL, Abraham D, Tóth A, Podesser BK, et al. Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning. International Journal of Molecular Sciences. 2021; 22(20):11064. https://doi.org/10.3390/ijms222011064

Chicago/Turabian Style

Bódi, Beáta, Patrick M. Pilz, Lilla Mártha, Miriam Lang, Ouafa Hamza, Miklós Fagyas, Petra L. Szabó, Dietmar Abraham, Attila Tóth, Bruno K. Podesser, and et al. 2021. "Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning" International Journal of Molecular Sciences 22, no. 20: 11064. https://doi.org/10.3390/ijms222011064

APA Style

Bódi, B., Pilz, P. M., Mártha, L., Lang, M., Hamza, O., Fagyas, M., Szabó, P. L., Abraham, D., Tóth, A., Podesser, B. K., Kiss, A., & Papp, Z. (2021). Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning. International Journal of Molecular Sciences, 22(20), 11064. https://doi.org/10.3390/ijms222011064

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Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning

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