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

Beáta Bódi,Lilla Mártha,Attila Oláh,Attila Tóth,Tamás Radovits,Árpád Kovács,Béla Merkely,Zoltán Papp,Bálint András Barta,Hajnalka Gulyás,Csaba Mátyás

doi:10.3390/antiox10111776

Beáta Bódi, Lilla Mártha + Show 9 more

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https://doi.org/10.3390/antiox10111776

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Abstract

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 (Fpassive) 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 Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) 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 pCa50 values in LV cardiomyocytes, and it decreased pCa50 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 Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function.

Highlights

The prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) and the burden of heart failure (HF) increase worldwide [1]
3-NT were higher in left ventricular (LV) and right ventricular (RV) tissue samples of Zucker Diabetic Fatty (ZDF) animals than in those of the Lean or Lean + Vard groups (Figure 1C,D)
CGMP levels and the extent of nitro-oxidative stress were tested by immunohistochemistry. cyclic guanosine monophosphate (cGMP) specific staining intensity was less in both LV and RV tissue samples of ZDF hearts than in those of the Lean or Lean + Vard groups (Figure 1A,B)

Summary

Introduction

The prevalence of metabolic disorders such as obesity and type 2 diabetes mellitus (T2DM) and the burden of heart failure (HF) increase worldwide [1]. Antioxidants 2021, 10, 1776 by diabetic cardiomyopathy presenting with left ventricular (LV) diastolic dysfunction: i.e., increased LV stiffness with elevated end-diastolic pressure and impaired LV filling [2]. LV diastolic dysfunction is a hallmark of HF with preserved LV ejection fraction (HFpEF), a type of HF with poor therapeutic responses for conventional HF medications [3]. Worsening right ventricular (RV) performance is a common, and poor prognostic feature of HFpEF with a hypothetical RV cardiomyocyte dysfunction [4,5]. Diabetic and hypertensive patients first develop signs of subclinical RV diastolic dysfunction and thereafter systolic impairment [6,7,8]. RV dilatation and dysfunction are more severe, and exercise capacity is worse in obese HFpEF patients than those in non-obese HFpEF patients, suggesting an obesity-related HFpEF subtype [10]

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