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Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat

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Abstract

Chronic angiotensin-converting enzyme inhibitor (ACEIs) treatment can suppress arrhythmogenesis. To examine whether the effect is more immediate and independent of suppression of pathological remodelling, we tested the antiarrhythmic effect of short-term ACE inhibition in healthy normotensive rats. Wistar rats were administered with enalaprilat (ENA, i.p., 5 mg/kg every 12 h) or vehicle (CON) for 2 weeks. Intraarterial blood pressure in situ was measured in A. carotis. Cellular shortening was measured in isolated, electrically paced cardiomyocytes. Standard 12-lead electrocardiography was performed, and hearts of anaesthetized open-chest rats were subjected to 6-min ischemia followed by 10-min reperfusion to examine susceptibility to ventricular arrhythmias. Expressions of calcium-regulating proteins (SERCA2a, cardiac sarco/endoplasmic reticulum Ca2+-ATPase; CSQ, calsequestrin; TRD, triadin; PLB, phospholamban; Thr17–PLB—phosphorylated PLB at threonine-17, FKBP12.6, FK506-binding protein, Cav1.2—voltage-dependent L-type calcium channel alpha 1C subunit) were measured by Western blot; mRNA levels of L-type calcium channel (Cacna1c), ryanodine receptor (Ryr2) and potassium channels Kcnh2 and Kcnq1 were measured by qRT-PCR. ENA decreased intraarterial systolic as well as diastolic blood pressure (by 20 %, and by 31 %, respectively, for both P < 0.05) but enhanced shortening of cardiomyocytes at basal conditions (by 34 %, P < 0.05) and under beta-adrenergic stimulation (by 73 %, P < 0.05). Enalaprilat shortened QTc interval duration (CON 78 ± 1 ms vs. ENA 72 ± 2 ms; P < 0.05) and significantly decreased the total duration of ventricular fibrillations (VF) and the number of VF episodes (P < 0.05). Reduction in arrhythmogenesis was associated with a pronounced upregulation of SERCA2a (CON 100 ± 20 vs. ENA 304 ± 13; P < 0.05) and complete absence of basal Ca2+/calmodulin-dependent phosphorylation of PLB at Thr17. Short-term ACEI treatment can provide protection against I/R injury-induced ventricular arrhythmias in healthy myocardium, and this effect is associated with increased SERCA2a expression.

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Acknowledgments

This work was supported by the grant APVV-0887-11 Molecular aspects of drug-induced heart failure and ventricular arrhythmias from the Slovak Research and Development Agency, the grants 1/0294/15 and 1/0564/13 from the Science Grant Agency (VEGA), Slovak Republic and by the grant of European Regional Development Fund—Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123), Czech Republic. The authors would like to thank Simona Kolembusova and Jan Tomasek for their excellent technical assistance.

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    1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic

      Marek Matus, Dana Kucerova, Adriana Adameova, Gabriel Doka, Katarina Turcekova, Jana Kmecova, Jan Kyselovic, Peter Krenek & Jan Klimas

    2. Institute of Pharmacology and Toxicology, University of Münster, Münster, Germany

      Dana Kucerova, Uwe Kirchhefer, Frank U. Mueller & Peter Boknik

    3. Department of Cardiovascular Diseases, International Clinical Research Center, St. Anne’s University Hospital and Masaryk University, Pekarska 53, 656 91, Brno, Czech Republic

      Peter Kruzliak

    4. Division of Endocrinology, Diabetes and Clinical Nutrition, UniversitätsSpital Zürich, University of Zurich, Zurich, Switzerland

      Katarina Turcekova

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    Matus, M., Kucerova, D., Kruzliak, P. et al. Upregulation of SERCA2a following short-term ACE inhibition (by enalaprilat) alters contractile performance and arrhythmogenicity of healthy myocardium in rat. Mol Cell Biochem 403, 199–208 (2015). https://doi.org/10.1007/s11010-015-2350-1

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