Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts

Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inh...

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Autores principales:	Beáta Bódi, Árpád Kovács, Hajnalka Gulyás, Lilla Mártha, Attila Tóth, Csaba Mátyás, Bálint András Barta, Attila Oláh, Béla Merkely, Tamás Radovits, Zoltán Papp
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	right ventricle HFpEF diabetic cardiomyopathy cardiomyocyte passive tension Ca<sup>2+</sup>-sensitivity of force production myofilament protein phosphorylation Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/04ef2fffcc6544f4a0bdcdfbf7c8833a
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spelling	oai:doaj.org-article:04ef2fffcc6544f4a0bdcdfbf7c8833a2021-11-25T16:28:21ZLong-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts10.3390/antiox101117762076-3921https://doaj.org/article/04ef2fffcc6544f4a0bdcdfbf7c8833a2021-11-01T00:00:00Zhttps://www.mdpi.com/2076-3921/10/11/1776https://doaj.org/toc/2076-3921Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (F<sub>passive</sub>) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca<sup>2+</sup>-activated force (F<sub>max</sub>) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca<sup>2+</sup>-sensitivity of isometric force production (pCa<sub>50</sub>) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa<sub>50</sub> values in LV cardiomyocytes, and it decreased pCa<sub>50</sub> below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and F<sub>passive</sub> levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa<sub>50</sub> values implicate different responses for the systolic function.Beáta BódiÁrpád KovácsHajnalka GulyásLilla MárthaAttila TóthCsaba MátyásBálint András BartaAttila OláhBéla MerkelyTamás RadovitsZoltán PappMDPI AGarticleright ventricleHFpEFdiabetic cardiomyopathycardiomyocyte passive tensionCa<sup>2+</sup>-sensitivity of force productionmyofilament protein phosphorylationTherapeutics. PharmacologyRM1-950ENAntioxidants, Vol 10, Iss 1776, p 1776 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	right ventricle HFpEF diabetic cardiomyopathy cardiomyocyte passive tension Ca<sup>2+</sup>-sensitivity of force production myofilament protein phosphorylation Therapeutics. Pharmacology RM1-950
spellingShingle	right ventricle HFpEF diabetic cardiomyopathy cardiomyocyte passive tension Ca<sup>2+</sup>-sensitivity of force production myofilament protein phosphorylation Therapeutics. Pharmacology RM1-950 Beáta Bódi Árpád Kovács Hajnalka Gulyás Lilla Mártha Attila Tóth Csaba Mátyás Bálint András Barta Attila Oláh Béla Merkely Tamás Radovits Zoltán Papp Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
description	Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (F<sub>passive</sub>) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca<sup>2+</sup>-activated force (F<sub>max</sub>) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca<sup>2+</sup>-sensitivity of isometric force production (pCa<sub>50</sub>) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa<sub>50</sub> values in LV cardiomyocytes, and it decreased pCa<sub>50</sub> below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and F<sub>passive</sub> levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa<sub>50</sub> values implicate different responses for the systolic function.
format	article
author	Beáta Bódi Árpád Kovács Hajnalka Gulyás Lilla Mártha Attila Tóth Csaba Mátyás Bálint András Barta Attila Oláh Béla Merkely Tamás Radovits Zoltán Papp
author_facet	Beáta Bódi Árpád Kovács Hajnalka Gulyás Lilla Mártha Attila Tóth Csaba Mátyás Bálint András Barta Attila Oláh Béla Merkely Tamás Radovits Zoltán Papp
author_sort	Beáta Bódi
title	Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
title_short	Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
title_full	Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
title_fullStr	Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
title_full_unstemmed	Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts
title_sort	long-term pde-5a inhibition improves myofilament function in left and right ventricular cardiomyocytes through partially different mechanisms in diabetic rat hearts
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/04ef2fffcc6544f4a0bdcdfbf7c8833a
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Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts

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