Mátyás Csaba, Németh Balázs Tamás, Oláh Attila, Hidi László, Birtalan Ede, Kellermayer Dalma, Ruppert Mihály, Korkmaz-Icöz Sevil, Kökény Gábor, Horváth Eszter Mária, Szabó Gábor, Merkely Béla, Radovits Tamás
Heart and Vascular Center, Semmelweis University, Városmajor u. 68., Budapest, 1122, Hungary.
Experimental Laboratory of Cardiac Surgery, Department of Cardiac Surgery, University of Heidelberg, INF 326. OG 2, 69120, Heidelberg, Germany.
Cardiovasc Diabetol. 2015 Oct 31;14:145. doi: 10.1186/s12933-015-0309-x.
Diabetes mellitus (DM) leads to the development of diabetic cardiomyopathy, which is associated with altered nitric oxide (NO)--soluble guanylate cyclase (sGC)--cyclic guanosine monophosphate (cGMP) signalling. Cardioprotective effects of elevated intracellular cGMP-levels have been described in different heart diseases. In the current study we aimed at investigating the effects of pharmacological activation of sGC in diabetic cardiomyopathy.
Type-1 DM was induced in rats by streptozotocin. Animals were treated either with the sGC activator cinaciguat (10 mg/kg/day) or with placebo orally for 8 weeks. Left ventricular (LV) pressure-volume (P-V) analysis was used to assess cardiac performance. Additionally, gene expression (qRT-PCR) and protein expression analysis (western blot) were performed. Cardiac structure, markers of fibrotic remodelling and DNA damage were examined by histology, immunohistochemistry and TUNEL assay, respectively.
DM was associated with deteriorated cGMP signalling in the myocardium (elevated phosphodiesterase-5 expression, lower cGMP-level and impaired PKG activity). Cardiomyocyte hypertrophy, fibrotic remodelling and DNA fragmentation were present in DM that was associated with impaired LV contractility (preload recruitable stroke work (PRSW): 49.5 ± 3.3 vs. 83.0 ± 5.5 mmHg, P < 0.05) and diastolic function (time constant of LV pressure decay (Tau): 17.3 ± 0.8 vs. 10.3 ± 0.3 ms, P < 0.05). Cinaciguat treatment effectively prevented DM related molecular, histological alterations and significantly improved systolic (PRSW: 66.8 ± 3.6 mmHg) and diastolic (Tau: 14.9 ± 0.6 ms) function.
Cinaciguat prevented structural, molecular alterations and improved cardiac performance of the diabetic heart. Pharmacological activation of sGC might represent a new therapy approach for diabetic cardiomyopathy.
糖尿病（DM）会导致糖尿病性心肌病的发生，这与一氧化氮（NO）-可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）信号通路的改变有关。细胞内cGMP水平升高对不同心脏病具有心脏保护作用。在本研究中，我们旨在探究sGC的药理学激活对糖尿病性心肌病的影响。
通过链脲佐菌素诱导大鼠患1型糖尿病。动物分别口服sGC激活剂西那吉酯（10 mg/kg/天）或安慰剂，持续8周。采用左心室（LV）压力-容积（P-V）分析评估心脏功能。此外，进行基因表达（qRT-PCR）和蛋白质表达分析（蛋白质印迹法）。分别通过组织学、免疫组织化学和TUNEL检测评估心脏结构、纤维化重塑标志物和DNA损伤。
糖尿病与心肌中cGMP信号通路恶化有关（磷酸二酯酶-5表达升高、cGMP水平降低和蛋白激酶G活性受损）。糖尿病中存在心肌细胞肥大、纤维化重塑和DNA片段化，这与左心室收缩功能受损（预负荷可募集搏功（PRSW）：49.5±3.3 vs. 83.0±5.5 mmHg，P<0.05）和舒张功能受损（左心室压力衰减时间常数（Tau）：17.3±0.8 vs. 10.3±0.3 ms，P<0.05）相关。西那吉酯治疗有效预防了糖尿病相关的分子、组织学改变，并显著改善了收缩功能（PRSW：66.8±3.6 mmHg）和舒张功能（Tau：14.9±0.6 ms）。
西那吉酯预防了糖尿病心脏的结构、分子改变并改善了心脏功能。sGC的药理学激活可能代表糖尿病性心肌病的一种新治疗方法。
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