Bódi Beáta, Kovács Árpád, Gulyás Hajnalka, Mártha Lilla, Tóth Attila, Mátyás Csaba, Barta Bálint András, Oláh Attila, Merkely Béla, Radovits Tamás, Papp Zoltán
Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Doctoral School of Pharmaceutical Sciences, University of Debrecen, 4032 Debrecen, Hungary.
Antioxidants (Basel). 2021 Nov 6;10(11):1776. doi: 10.3390/antiox10111776.
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) 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-activated force (F) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca-sensitivity of isometric force production (pCa) 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 values in LV cardiomyocytes, and it decreased pCa 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 levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa values implicate different responses for the systolic function.
射血分数保留的心力衰竭（HFpEF）和右心室（RV）功能障碍是糖尿病性心肌病的常见并发症。在此，我们旨在描述糖尿病HFpEF模型中右心室和左心室（LV）的重塑情况以及通过给予伐地那非（一种长效磷酸二酯酶-5A（PDE-5A）抑制剂）对其进行预防的效果。Zucker糖尿病肥胖（ZDF）大鼠和对照ZDF瘦型（Lean）雄性大鼠每天口服10 mg/kg伐地那非（ZDF + Vard；Lean + Vard），持续25周。采用体外力量测量、生化和组织化学分析来评估心肌细胞功能和信号传导。伐地那非治疗可提高ZDF动物左、右心室中的环磷酸鸟苷（cGMP）水平，并降低3-硝基酪氨酸（3-NT）水平，但对Lean动物无此作用。ZDF大鼠左心室和右心室心肌细胞的被动张力（F）高于接受预防性伐地那非治疗的大鼠。四个实验组的肌联蛋白总体磷酸化水平无差异。ZDF动物左心室和右心室心肌细胞的最大钙激活力（F）得以保留。ZDF大鼠左心室（而非右心室）心肌细胞等长力产生的钙敏感性（pCa）显著高于Lean或Lean + Vard组的相应心肌细胞。相应地，ZDF动物左心室（而非右心室）心肌细胞中心肌肌钙蛋白I（cTnI）和肌球蛋白结合蛋白-C（cMyBP-C）的磷酸化水平低于Lean或Lean + Vard组的相应心肌细胞。伐地那非治疗使左心室心肌细胞的pCa值恢复正常，并使ZDF + Vard组右心室心肌细胞的pCa值降至对照水平以下。我们的数据表明，长期抑制PDE-5A后，糖尿病大鼠心脏中左心室和右心室心肌细胞的肌丝蛋白改变部分重叠。虽然cGMP、3-NT和F水平的一致模式预示着伐地那非治疗对两个心室舒张功能的相同作用，但cTnI、cMyBP-C磷酸化水平和pCa值的不均衡表明对收缩功能的反应不同。
