Katare Rajesh, Pearson James T, Lew Jason Kar-Sheng, Wei Melanie, Tsuchimouchi Hirotsugu, Du Cheng-Kun, Zhan Dong-Yun, Umetani Keiji, Shirai Mikiyasu, Schwenke Daryl O
Department of Physiology, HeartOtago, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand.
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
Front Physiol. 2018 Jun 6;9:696. doi: 10.3389/fphys.2018.00696. eCollection 2018.
The causal factors underpinning the onset and progression of diabetic heart disease (DHD) remain to be fully elucidated. Myocardial function is critically dependent on optimal coronary blood flow. Considering vascular disease occurs early in diabetes due to endothelial dysfunction, this study aimed to determine whether impaired coronary perfusion contributes to the origins of myocardial dysfunction in DHD, or whether coronary and cardiac dysfunction are independent pathologies associated with diabetes. Synchrotron radiation microangiography was used to image the coronary circulation of type-2 diabetic db/db and non-diabetic db/+ mice at 8, 16, and 24 weeks of age. We further assessed vascular function based on the vasodilatory responses to acetylcholine (ACh, 3 μg/kg/min), sodium nitroprusside (SNP, 5 μg/kg/min) and the Rho-kinase inhibitor, fasudil (20 mg/kg, i.v.). Cardiac function was assessed using echocardiography, and cardiac eNOS and ROCK expression were measured using immunohistochemistry. Coronary and cardiac function were normal in 8-week-old diabetic mice. However, by 16 weeks of age, diabetic mice had advanced cardiac dysfunction. In comparison, normal coronary perfusion was preserved in diabetes until 24 weeks of age. Moreover, only the 24-week-old diabetic mice showed clear evidence of advanced coronary vascular dysfunction, based on (i) the absence of a vasodilatory response to ACh, and (ii) an exaggerated vasodilatory response to fasudil. Interestingly, fasudil also restored normal coronary perfusion in the 24-week-old diabetic heart by restoring blood flow to previously constricted vessels (diameter < 100 μm). Importantly, there was a ubiquitous decrease, and increase, in the cardiac expression of eNOS and ROCK, respectively. These results suggest that both cardiac and coronary dysfunction appear to have independent origins associated with diabetes and Rho-kinase pathway may be playing a role in the onset and progression of DHD.
糖尿病性心脏病（DHD）发病和进展的因果因素仍有待充分阐明。心肌功能严重依赖于最佳的冠状动脉血流量。鉴于糖尿病早期因内皮功能障碍会发生血管疾病，本研究旨在确定冠状动脉灌注受损是否导致DHD中心肌功能障碍的起源，或者冠状动脉和心脏功能障碍是否为与糖尿病相关的独立病理状态。利用同步辐射微血管造影术对8周、16周和24周龄的2型糖尿病db/db小鼠和非糖尿病db/+小鼠的冠状动脉循环进行成像。我们还基于对乙酰胆碱（ACh，3μg/kg/min）、硝普钠（SNP，5μg/kg/min）和Rho激酶抑制剂法舒地尔（20mg/kg，静脉注射）的血管舒张反应评估血管功能。使用超声心动图评估心脏功能，并使用免疫组织化学法测量心脏内皮型一氧化氮合酶（eNOS）和Rho相关卷曲螺旋蛋白激酶（ROCK）的表达。8周龄的糖尿病小鼠冠状动脉和心脏功能正常。然而，到16周龄时，糖尿病小鼠出现了严重的心脏功能障碍。相比之下，糖尿病小鼠在24周龄之前冠状动脉灌注保持正常。此外，仅24周龄的糖尿病小鼠表现出明显的严重冠状动脉血管功能障碍的证据，基于（i）对ACh无血管舒张反应，以及（ii）对法舒地尔的血管舒张反应过度。有趣的是，法舒地尔还通过使先前收缩的血管（直径<100μm）恢复血流，使24周龄糖尿病心脏的冠状动脉灌注恢复正常。重要的是，心脏中eNOS的表达普遍下降，而ROCK的表达普遍增加。这些结果表明，心脏和冠状动脉功能障碍似乎都有与糖尿病相关的独立起源，并且Rho激酶途径可能在DHD的发病和进展中起作用。
