Biology subjects

Pavelec, C. M.

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

3 recordsLinked to original sources

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↗