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Fropofol prevents disease progression in mice with hypertrophic cardiomyopathy.

ABSTRACT:

Aims

Increased myofilament contractility is recognized as a crucial factor in the pathogenesis of hypertrophic cardiomyopathy (HCM). Direct myofilament desensitization might be beneficial in preventing HCM disease progression. Here, we tested whether the small molecule fropofol prevents HCM phenotype expression and disease progression by directly depressing myofilament force development.

Methods and results

Force, intracellular Ca2+, and steady-state activation were determined in isolated trabecular muscles from wild-type (WT) and transgenic HCM mice with heterozygous human α-myosin heavy chain R403Q mutation (αMHC 403/+). αMHC 403/+ HCM mice were treated continuously with fropofol by intraperitoneal infusion for 12 weeks. Heart tissue was analysed with histology and real-time PCR of prohypertrophic and profibrotic genes. Fropofol decreased force in a concentration-dependent manner without significantly altering [Ca2+]i in isolated muscles from both WT and αMHC 403/+ HCM mouse hearts. Fropofol also depressed maximal Ca2+-activated force and increased the [Ca2+]i required for 50% activation during steady-state activation. In whole-animal studies, chronic intra-abdominal administration of fropofol prevented hypertrophy development and diastolic dysfunction. Chronic fropofol treatment also led to attenuation of prohypertrophic and profibrotic gene expression, reductions in cell size, and decreases in tissue fibrosis.

Conclusions

Direct inhibition of myofilament contraction by fropofol prevents HCM disease phenotypic expression and progression, suggesting that increased myofilament contractile force is the primary trigger for hypertrophy development and HCM disease progression.

SUBMITTER: Huang Y

PROVIDER: S-EPMC8453292 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlthough the genetic causes of hypertrophic cardiomyopathy (HCM) are widely recognized, considerable lag in the development of targeted therapeutics has limited interventions to symptom palliation. This is in part attributable to an incomplete understanding of how point mutations trigger pathogenic remodeling. As a further complication, similar mutations within sarcomeric genes can result in differential disease severity, highlighting the need to understand the mechanism of progression at the molecular level. One pathway commonly linked to HCM progression is calcium homeostasis dysregulation, though how specific mutations disrupt calcium homeostasis remains unclear.MethodsTo evaluate the effects of early intervention in calcium homeostasis, we used 2 mouse models of sarcomeric HCM (cardiac troponin T R92L and R92W) with differential myocellular calcium dysregulation and disease presentation. Two modes of intervention were tested: inhibition of the autoactivated calcium-dependent kinase (calmodulin kinase II [CaMKII]) via the AC3I peptide and diltiazem, an L-type calcium channel antagonist. Two-dimensional echocardiography was used to determine cardiac function and left ventricular remodeling, and atrial remodeling was monitored via atrial mass. Sarcoplasmic reticulum Ca2+ATPase activity was measured as an index of myocellular calcium handling and coupled to its regulation via the phosphorylation status of phospholamban.ResultsWe measured an increase in phosphorylation of CaMKII in R92W animals by 6 months of age, indicating increased autonomous activity of the kinase in these animals. Inhibition of CaMKII led to recovery of diastolic function and partially blunted atrial remodeling in R92W mice. This improved function was coupled to increased sarcoplasmic reticulum Ca2+ATPase activity in the R92W animals despite reduction of CaMKII activation, likely indicating improvement in myocellular calcium handling. In contrast, inhibition of CaMKII in R92L animals led to worsened myocellular calcium handling, remodeling, and function. Diltiazem-HCl arrested diastolic dysfunction progression in R92W animals only, with no improvement in cardiac remodeling in either genotype.ConclusionsWe propose a highly specific, mutation-dependent role of activated CaMKII in HCM progression and a precise therapeutic target for clinical management of HCM in selected cohorts. Moreover, the mutation-specific response elicited with diltiazem highlights the necessity to understand mutation-dependent progression at a molecular level to precisely intervene in disease progression.