Biology subjects

Pavelec, C. M.

Publications and source records attributed to Pavelec, C. M..

4 recordsLinked to original sources

bioRxiv2026

Therapeutic targeting of MYBPC3 mutation-specific hypertrophic cardiomyopathy guided by network modeling

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death with genotype positive cases most commonly associated with mutations of cardiac myosin binding protein-C (MYBPC3). Recently approved drugs for HCM target the myofilaments rather than the aberrant molecular signaling pathways that drive long-term remodeling. Here, we identified a patient with familial HCM that was associated with a MYBPC3 W1078 truncation mutation. A CRISPR knock-in mouse model of the orthologous mutation MYBPC3 W1082 exhibited marked cardiac hypertrophy including wall thickening, reduced ejection fraction, and decreased survival. To identify pathways, mechanisms, and potential candidate therapeutics, we integrated the MYBPC3 mutation into a computational network model of the signaling underlying familial cardiomyopathy. The network model predicted that the MYBPC3 mutation drove hypertrophy through mTOR/PI3K pathways, consistent with the results of RNA sequencing of cardiomyocytes of MYBPC3W1082*/W1082* mice. A virtual drug screen using FDA-approved drugs predicted that the mTOR inhibitor, Rapamycin, could mitigate mutation-induced hypertrophy. We then experimentally validated the effects of Rapamycin on hypertrophic responses using cultured cardiomyocytes. Further, Rapamycin attenuated cardiac hypertrophy and fibrosis of MYBPC3W1082*/W1082* mice in vivo. mTOR inhibitors (rapamycin and everolimus) were associated with a decreased incidence of cardiac hypertrophy associated diagnostic codes in patients in the FDA Adverse Events Reporting System. Query of electronic health records and echocardiograms from a University of Virginia cohort of patients treated with mTOR or calcineurin inhibitors showed that patients prescribed everolimus or tacrolimus had reduced LV wall thicknesses. Together, these studies suggest that targeting mTOR as a translationally relevant target for a mutation-induced hypertrophic cardiomyopathy, as well as demonstrating the utility of guiding precision therapies by iterating between network models and experimental validation.

physiology↗

bioRxiv2024

Sarm1-Dependent Metabolic Reprogramming of Schwann Cells Following Nerve Injury

Schwann cells (SCs) transition into a Repair state after peripheral nerve injury; however, the early SC injury response preceding this transition remains poorly understood. We demonstrate that Sarm1, a key regulator of axon degeneration, is expressed and upregulated in SCs after nerve injury. Cell-type-specific Sarm1 knockout SCs exhibit enhanced axon protection in vitro, and SC- and glia-specific Sarm1 deletion confers axon protection in mouse sciatic nerve and Drosophila wing injury models. Single-nucleus RNA sequencing revealed that Sarm1-deficient SCs are enriched in a distinct cluster expressing genes with developmental roles in axon and myelin protection, with increased oxidative phosphorylation gene expression across all injured SC states. We propose that Sarm1 gates the transition from a Protection-Associated Schwann Cell (PASC) state to a Repair SC state, establishing Sarm1 as a multi-functional regulator with implications for peripheral neuropathies and neurodegenerative diseases.

neuroscience↗

bioRxiv2024

Nitrosation of CD36 regulates endothelial function and serum lipids

During obesity, endothelial cells (ECs) become lipid laden leading to endothelial dysfunction. We demonstrate endothelium downregulates caveolin-1 (Cav1) in mouse and human in response to obesity. Using an EC-specific Cav1 knockout mouse, we find mice are hyperlipidemic regardless of diet, but retain endothelial cell function. Whereas initially this was thought to be due to Cav1 mediate endocytosis, we find instead the mice have significantly increased nitric oxide (NO) in response to the lack of Cav1. The presence or absence of NO toggled inversely EC lipid content and plasma lipid in mice. We found the fatty acid translocase CD36 was directly nitrosated by endogenous NO at the same cysteines that are palmitoylated on CD36. The nitrosation of CD36 prevented its trafficking to the plasma membrane and decreased lipid uptake. The physiological effect of this mechanism was a reliance on NO for endothelial function. This work suggests that CD36 nitrosation occurs as a protective mechanism to prevent EC lipotoxicity and preserve function. TeaserNitric oxide regulates serum lipids and endothelial cell lipid content through nitrosation of CD36.

molecular biology↗

bioRxiv2023

Pannexin 1 Channels Control Cardiomyocyte Metabolism and Neutrophil Recruitment During Non-Ischemic Heart Failure

Pannexin 1 (PANX1), a ubiquitously expressed ATP release membrane channel, has been shown to play a role in inflammation, blood pressure regulation, and myocardial infarction. However, a possible role of PANX1 in cardiomyocytes in the progression of heart failure has not yet been investigated. We generated a novel mouse line with constitutive deletion of PANX1 in cardiomyocytes (Panx1MyHC6). PANX1 deletion in cardiomyocytes had no effect on unstressed heart function but increased the glycolytic metabolism both in vivo and in vitro. In vitro, treatment of H9c2 cardiomyocytes with isoproterenol led to PANX1-dependent release of ATP and Yo-Pro-1 uptake, as assessed by pharmacological blockade with spironolactone and siRNA-mediated knock-down of PANX1. To investigate non-ischemic heart failure and the preceding cardiac hypertrophy we administered isoproterenol, and we demonstrate that Panx1MyHC6 mice were protected from systolic and diastolic left ventricle volume increases and cardiomyocyte hypertrophy. Moreover, we found that Panx1MyHC6 mice showed decreased isoproterenol-induced recruitment of immune cells (CD45+), particularly neutrophils (CD11b+, Ly6g+), to the myocardium. Together these data demonstrate that PANX1 deficiency in cardiomyocytes impacts glycolytic metabolism and protects against cardiac hypertrophy in non-ischemic heart failure at least in part by reducing immune cell recruitment. Our study implies PANX1 channel inhibition as a therapeutic approach to ameliorate cardiac dysfunction in heart failure patients.

physiology↗