Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 179, Issue 10, Pages 2240-2258Publisher
WILEY
DOI: 10.1111/bph.15749
Keywords
BGP-15; diastolic dysfunction; hypercholesterolemia; protein kinase G; titin
Categories
Funding
- Ministry of Human Capacities, Hungary [20391-3/2018/FEKUSTRAT]
- National Research, Development and Innovation Fund of Hungary [2020-4.1.1-TKP2020, TKP2020-IKA-04]
- Die Deutsche Forschungsgemeinschaft [HA 7512/2-1]
- European Union
- European Social Fund [GINOP-2.3.2-15-2016-00043]
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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. The findings suggest that BGP-15 may have potential clinical utility in the treatment of diastolic dysfunction.
Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusions and Implications 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.
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