Tate Mitchel, Perera Nimna, Prakoso Darnel, Willis Andrew M, Deo Minh, Oseghale Osezua, Qian Hongwei, Donner Daniel G, Kiriazis Helen, De Blasio Miles J, Gregorevic Paul, Ritchie Rebecca H
Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
Heart Failure Pharmacology, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.
Front Pharmacol. 2021 Oct 8;12:719290. doi: 10.3389/fphar.2021.719290. eCollection 2021.
Diabetes is a major contributor to the increasing burden of heart failure prevalence globally, at least in part due to a disease process termed diabetic cardiomyopathy. Diabetic cardiomyopathy is characterised by cardiac structural changes that are caused by chronic exposure to the diabetic milieu. These structural changes are a major cause of left ventricular (LV) wall stiffness and the development of LV dysfunction. In the current study, we investigated the therapeutic potential of a cardiac-targeted bone morphogenetic protein 7 (BMP7) gene therapy, administered once diastolic dysfunction was present, mimicking the timeframe in which clinical management of the cardiomyopathy would likely be desired. Following 18 weeks of untreated diabetes, mice were administered with a single tail-vein injection of recombinant adeno-associated viral vector (AAV), containing the BMP7 gene, or null vector. Our data demonstrated, after 8 weeks of treatment, that rAAV6-BMP7 treatment exerted beneficial effects on LV functional and structural changes. Importantly, diabetes-induced LV dysfunction was significantly attenuated by a single administration of rAAV6-BMP7. This was associated with a reduction in cardiac fibrosis, cardiomyocyte hypertrophy and cardiomyocyte apoptosis. In conclusion, BMP7 gene therapy limited pathological remodelling in the diabetic heart, conferring an improvement in cardiac function. These findings provide insight for the potential development of treatment strategies urgently needed to delay or reverse LV pathological remodelling in the diabetic heart.
糖尿病是全球心力衰竭患病率不断增加的主要促成因素，至少部分原因是一种称为糖尿病性心肌病的疾病过程。糖尿病性心肌病的特征是由长期暴露于糖尿病环境引起的心脏结构变化。这些结构变化是左心室（LV）壁僵硬和LV功能障碍发展的主要原因。在本研究中，我们研究了心脏靶向骨形态发生蛋白7（BMP7）基因治疗的治疗潜力，在出现舒张功能障碍后给予一次治疗，模拟可能需要对心肌病进行临床管理的时间范围。在未经治疗的糖尿病18周后，给小鼠单次尾静脉注射含有BMP7基因的重组腺相关病毒载体（AAV）或空载体。我们的数据表明，在治疗8周后，rAAV6-BMP7治疗对LV功能和结构变化产生了有益影响。重要的是，单次给予rAAV6-BMP7可显著减轻糖尿病诱导的LV功能障碍。这与心脏纤维化、心肌细胞肥大和心肌细胞凋亡的减少有关。总之，BMP7基因治疗限制了糖尿病心脏的病理重塑，改善了心脏功能。这些发现为迫切需要的治疗策略的潜在发展提供了见解，以延迟或逆转糖尿病心脏的LV病理重塑。
