Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy
Telmisartan and thiorphan combination treatment attenuates fibrosis and apoptosis in preventing diabetic cardiomyopathy
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DOI：
10.1093/cvr/cvy226
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发表时间：
2019-02-01
影响因子：
10.8
通讯作者：
Gaikwad, Anil Bhanudas
中科院分区：
文献类型：
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作者：
Malek, Vajir;Gaikwad, Anil Bhanudas
目的LCZ 696是第一代双重血管紧张素受体-脑啡肽酶抑制剂（ARNi），可有效治疗心力衰竭患者。然而，ARNis在治疗糖尿病性心肌病中的作用知之甚少。本研究评价了替米沙坦[血管紧张素受体阻滞剂（ARB）]和thiorphan [脑啡肽酶抑制剂（NEPi）]的新型组合在改善糖尿病心肌病中的功效，同时探索相关的潜在分子机制。雄性Wistar大鼠。4周后，对糖尿病大鼠进行硫啡烷（0.1mg/kg/天，p.o.）或替米沙坦（10 mg/kg/天，p.o.）单药治疗或其组合，持续4周。代谢和形态学改变、心室功能衰竭以及压力反射减弱表明糖尿病心脏并发症的发生。除形态学改变外，所有病理学后果均通过替米沙坦和噻奥芬联合治疗预防。糖尿病大鼠表现出显着的调节利钠肽系统，一个关键的血液动力学调节，这是正常的联合治疗。组织学研究显示心肌纤维化增强，表现为%PSR阳性面积增加，联合治疗对这些指标的改善最佳。更重要的是，当治疗糖尿病性心肌病大鼠时，与相应的单药治疗相比，噻奥芬和替米沙坦联合治疗在减弱炎症（NF-B/MCP-1）、促纤维化（TGF-/Smad 7）和凋亡（PARP/Caspase-3）级联反应方面具有上级优势。此外，糖尿病心脏染色质处于活跃的转录状态，表现为组蛋白乙酰化（H2 AK 5Ac、H2 BK 5Ac、H3 K9 Ac和H4 K8 Ac）和组蛋白乙酰转移酶（PCAF和Ac-CBP）水平升高。有趣的是，联合治疗是足够强大的正常化这些alternation.Conclusion新ARB和NEPi组合对糖尿病心肌病的保护作用可以归因于抑制炎症，促纤维化，和凋亡级联。此外，逆转组蛋白乙酰化有助于其保护作用。
Aims LCZ696, a first-generation dual angiotensin receptor-neprilysin inhibitor (ARNi), is effective in treating heart failure patients. However, the role of ARNis in treating diabetic cardiomyopathy is poorly understood. This study evaluates the efficacy of a novel combination of telmisartan [angiotensin receptor blocker (ARB)] and thiorphan [neprilysin inhibitor (NEPi)] in ameliorating diabetic cardiomyopathy while, at the same time, exploring the relevant underlying molecular mechanism(s).Methods and results Diabetes was induced by administration of streptozotocin (55mg/kg, i.p.) in male Wistar rats. After 4 weeks, diabetic rats were subjected to either thiorphan (0.1mg/kg/day, p.o.) or telmisartan (10mg/kg/day, p.o.) monotherapy, or their combination, for a period of 4 weeks. Metabolic and morphometric alterations, failing ventricular functions, and diminished baroreflex indicated development of diabetic cardiac complications. Apart from morphometric alterations, all pathological consequences were prevented by telmisartan and thiorphan combination therapy. Diabetic rats exhibited significant modulation of the natriuretic peptide system, a key haemodynamic regulator; this was normalized by combination therapy. Histopathological studies showed augmented myocardial fibrosis, demonstrated by increased % PSR-positive area, with combination therapy giving the best improvement in these indices. More importantly, the combination of thiorphan and telmisartan was superior in attenuating inflammatory (NF-B/MCP-1), profibrotic (TGF-/Smad7) and apoptotic (PARP/Caspase-3) cascades compared to respective monotherapies when treating rats with diabetic cardiomyopathy. In addition, diabetic heart chromatin was in a state of active transcription, indicated by increased histone acetylation (H2AK5Ac, H2BK5Ac, H3K9Ac, and H4K8Ac) and histone acetyltransferase (PCAF and Ac-CBP) levels. Interestingly, combination treatment was sufficiently potent to normalize these alterations.Conclusion The protective effect of novel ARB and NEPi combination against diabetic cardiomyopathy can be attributed to inhibition of inflammatory, profibrotic, and apoptotic cascades. Moreover, reversal of histone acetylation assists its protective effect.