Department of Pharmacology and Pharmacotherapy, Faculty of General Medicine, University of Debrecen, Debrecen, Hungary.
Institut für Forschung und Lehre (IFL), Department of Molecular and Experimental Cardiology, Ruhr University Bochum, Bochum, Germany.
Br J Pharmacol. 2022 May;179(10):2240-2258. doi: 10.1111/bph.15749. Epub 2022 Feb 5.
The small molecule BGP-15 has been reported to alleviate symptoms of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy.
Rabbits were maintained on standard chow (control) or atherogenic diet (hypercholesterolemic) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed and key molecules in the protein kinase G (PKG) pathway were examined by enzyme-linked immunosorbent assay (ELISA) and western blot. Passive force generation was investigated in skinned cardiomyocytes.
Both acute and chronic BGP-15 treatments improved the diastolic performance of the diseased heart. However, vasorelaxation and serum lipid markers were unaffected. Myocardial cyclic guanosine monophosphate (cGMP) levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group and PDE1 was inhibited. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased and PKG-dependent N2B-titin phosphorylation elevated.
BGP-15 treatment improves diastolic function, reduces cardiomyocyte stiffness and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG pathway. As BGP-15 has been proven to be safe, it may be clinically useful in the treatment of diastolic dysfunction.
小分子 BGP-15 已被报道可缓解心力衰竭症状并改善小鼠模型中的肌肉功能。在此，我们研究了 BGP-15 在动脉粥样硬化性心肌病兔模型中的急性和慢性作用。
兔子被维持在标准饮食（对照）或动脉粥样硬化饮食（高胆固醇血症）中 16 周。通过静脉内（一次）或口服（16 周）给予 BGP-15，以评估急性和慢性作用。通过超声心动图评估心功能，通过酶联免疫吸附测定（ELISA）和 Western blot 评估内皮依赖性血管舒张功能，并检测蛋白激酶 G（PKG）途径中的关键分子。在去皮心肌细胞中研究被动力产生。
急性和慢性 BGP-15 治疗均改善了患病心脏的舒张功能。然而，血管舒张和血清脂质标志物不受影响。BGP-15 治疗组心肌环鸟苷酸（cGMP）水平升高，PKG 活性和磷蛋白 Ser16 磷酸化保持不变。BGP-15 治疗组 PDE5 表达减少，PDE1 被抑制。BGP-15 治疗组的心肌细胞被动张力降低，titin N2BA/N2B 同工型比例增加，PKG 依赖性 N2B-titin 磷酸化增加。
BGP-15 治疗通过增加 cGMP-PKG 途径的活性，改善了动脉粥样硬化性心肌病兔模型的舒张功能，降低了心肌细胞硬度，并恢复了 titin 的顺应性。由于 BGP-15 已被证明是安全的，因此它在治疗舒张功能障碍方面可能具有临床应用价值。
