Nicotinic‐acid derivative BGP‐15 improves diastolic function in a rabbit model of atherosclerotic cardiomyopathy

Abstract

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.

Drug Candidate BGP-15 Prevents Isoproterenol-Induced Arrhythmias and Alters Heart Rate Variability (HRV) in Telemetry-Implanted Rats

“…Transmitral A wave was also decreased after the treatment, corresponding to our previous findings that BGP-15 has negative tropic effects on the human atria [ 28 ]. Similar outcomes were obtained from the 2-week studies, as BGP-15 treatment did not affect systolic parameters (EF, CO), but improved diastolic function, corresponding to our previous results in different animal models [ 25 , 29 ]. In addition, in the 2-week studies, we found worsened diastolic function (E/A, DecT) and significantly elevated LV mass in the ISO group, in accordance with the literature data [ 47 ].…”

“…The Ca 2+ -transients measured in the presence of BGP-15 tended to decrease when compared to ISO controls, showing that BGP-15 may partly affect Ca 2+ overload in cardiomyocytes. Interestingly, BGP-15 caused an increase in diastolic (and resting) sarcomere length, which might be a result of its actions on titin phosphorylation, which was previously shown by our team [ 29 ].…”

“…Considering these results, we propose some possible mechanisms by which BGP-15 prevents arrhythmogenesis. Firstly, we have recently shown that BGP-15 increases cardiac cGMP-PKG signaling [ 29 ]. PKG exerts cardioprotection by improving the diastolic function [ 57 ], but also modulates ATP-sensitive potassium channels (K(ATP) channels) via the inhibition of the (Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) pathway, a major contributor to arrhythmogenesis [ 58 ].…”

“…As phospholamban is a key regulator of cardiac contractility and modulates SR Ca 2+ sequestration by inhibiting the sarco-endoplasmic reticulum Ca-ATPase (SERCA) in its dephosphorylated state, BGP-15 may act by restoring SERCA activity [ 26 , 27 ]. Our team has previously shown that BGP-15 enhances cyclic guanosine monophosphate (cGMP)—protein kinase G (PKG) signaling, alters myocardial mechanics, and furthermore, decreases inotropy in paced human right atrial samples [ 28 , 29 ].…”

Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects

“…3). Increased activity and reduced oxidation of PKGIα led to increase phosphorylation of different myofilament proteins including titin and troponin I, which are known to be significantly hypophosphorylated in HFpEF patients and animal models [31][32][33]50,51,[178][179][180][181][182][183]. In line with that, increasing PKG activity improved deranged titin N2-Bus phosphorylation thereby lowering titin N2-B unique sequence (N2-Bus) bending rigidity and improve passive stiffness [31,50,178,181].…”