Biology subjects

Savko, C.

Publications and source records attributed to Savko, C..

4 recordsLinked to original sources

bioRxiv2024

The PIDDosome controls cardiomyocyte polyploidization during postnatal heart development

The adult mammalian heart is characterized by post-mitotic polyploid cardiomyocytes (CMs). Understanding how CMs regulate cell cycle exit and ploidy can help developing new heart regenerative therapies. Here, we uncover that the PIDDosome, a multi-protein complex activating the endopeptidase Caspase-2, helps to implement a CM-specific differentiation program that limits ploidy during postnatal heart development. DNA content analyses show that PIDDosome-loss causes a cell-autonomous increase in nuclear and cellular CM ploidy. Remarkably, increased ploidy does not affect cardiac structure nor function. PIDDosome-imposed ploidy restriction commences at postnatal day 7 (P7), reaching a plateau on P14. PIDDosome activation requires ANKRD26, targeting PIDD1 to mother centrioles. Opposite to prior observations in liver development, the PIDDosome limits CM polyploidization in a p53-independent manner but reliant on p21/Cdkn1a, a notion supported by nuclear RNA sequencing and genetic deletion experiments. Our results provide new insights how proliferation of polyploid CMs is restricted during postnatal heart development.

developmental biology↗

bioRxiv2024

Cardiac p16 Expression Following Vape Exposure with Nicotine Shows Sex-Specific Induction in Males but not Females

Vaping is marketed as a safe alternative to traditional cigarette smoking, but multiple studies demonstrate deleterious cardiopulmonary effects including cardiac function decline and fibrotic remodeling with alveolar size enlargement. Nicotine, a common constituent of vaping aerosol, stimulates p16 expression in pulmonary tissue but the impact on cardiac tissue remains unclear. In this study, mice were exposed to e-cigarette vape aerosol either containing nicotine (Vape Nicotine; VN) or without nicotine (Vape 0; V0). Non-exposed (No Vape; NoV) mice were used as controls. Cardiac effects were assessed by echocardiography, histology, and immunofluorescence to determine changes in function, morphology, p16, and Discoidin Domain Receptor 2 (DDR2). VN depressed cardiac function and increased collagen deposition relative to V0 and NoV. Interestingly, p16 expression was increased in cardiomyocytes and interstitial cells of male mice while remaining unchanged in females. In contrast to VN, V0 had no significant impact on cardiac function or p16 expression in males. Furthermore, collagen deposition in the V0 group was significantly lower than the VN group. Subsequent cardiac fibroblast analysis using DDR2 revealed increased expression within the V0 group relative to VN and NoV. Collectively, these findings show collagen accumulation as well as p16 expression prompted by vaping is mediated by nicotine as a constituent of vape juice. In contrast, vape aerosol alone promotes accrual of cardiac fibroblasts without concomitant changes in collagen accumulation or p16 expression. These results are the first to identify p16 induction with pathologic collagen deposition by exposure to vape aerosol containing nicotine in male cardiac tissue. The underlying basis for sex-specific differences in cardiac responses to vape aerosol exposure warrant further investigation, particularly those involving cellular and molecular changes that may lead to pathologic changes later in life.

molecular biology↗

bioRxiv2024

Myocardial infarction injury is exacerbated by nicotine in vape aerosol exposure

RationaleVaping is touted as a safer alternative to traditional cigarette smoking but the full spectrum of harm reduction versus comparable risk remains unresolved. Elevated bioavailability of nicotine in vape aerosol together with known risks of nicotine exposure may result in previously uncharacterized cardiovascular consequences of vaping. ObjectiveAssess the impact of nicotine exposure via vape aerosol inhalation upon myocardial response to infarction injury. Methods and ResultsFlavored vape juice containing nicotine (5 mg / ml) or vehicle alone (0 mg) was delivered using identical 4-week treatment protocols. Mice were subjected to acute myocardial infarction injury and evaluated for outcomes of cardiac structure and function. Findings reveal that nicotine exposure leads to worse outcomes with respect to contractile performance regardless of sex. Non-myocyte interstitial cell accumulation following infarction significantly increased with exposure to vape aerosol alone, but a comparable increase was not present when nicotine was included. ConclusionsMyocardial function after infarction is significantly decreased after exposure to nicotine vape aerosol irrespective of sex. Comparable loss of contractile function was not observed in mice exposed to vape aerosol alone, highlighting the essential role of nicotine in loss of contractile function. Increased vimentin immunoreactivity was observed in the vape alone group compared to control and vape nicotine. The correlation between vaping, interstitial cell responses, and cardiac remodeling leading to impaired contractility warrants further investigation. Public health experts seeking to reduce vaping-related health risks should consider messaging that highlights the increased cardiovascular risk especially with nicotine-containing aerosols.

molecular biology↗

bioRxiv2021

Fundamentals of Vaping-Associated Pulmonary Injury Leading to Severe Respiratory Distress

Vaping of flavored liquids has been touted as safe alternative to traditional cigarette smoking with decreased health risks. The popularity of vaping has dramatically increased over the last decade, particularly among teenagers who incorporate vaping into their daily life as a social activity. Despite widespread and increasing adoption of vaping among young adults there is little information on long term consequences of vaping and potential health risks. This study demonstrates Vaping-Induced Pulmonary Injury (VAPI) using commercial JUUL pens with flavored vape juice using an inhalation exposure murine model. Profound pathological changes to upper airway, lung tissue architecture, and cellular structure are evident within 9 weeks of exposure. Marked histologic changes include increased parenchyma tissue density, cellular infiltrates proximal to airway passages, alveolar rarefaction, increased collagen deposition, and bronchial thickening with elastin fiber disruption. Transcriptional reprogramming includes significant changes to gene families coding for xenobiotic response, glycerolipid metabolic processes, and oxidative stress. Cardiac contractile performance for systemic output is moderately but significantly impaired, and the shows severe pulmonary side structural remodeling with chamber enlargement. This VAPI model with pulmonary circuit failure demonstrates mechanistic underpinnings of vaping-related pathologic injury.

molecular biology↗