Evaluation of Sarcospan as a Genetic Factor Contributing to Cardiometabolic Risk in Smokers

Objective: Susceptibility of the cardiovascular system to smoking differs amongst individuals and genetic variations in proteins that affect lipid metabolism and risk of type 2 diabetes development may contribute to increased susceptibility of smokers. The sarcospan (SSPN) protein has been found decreased in the hearts and lungs of smokers and influences body-mass index and glucose tolerance. Sarcospan (SSPN) is an integral member of the dystrophin-glycoprotein complex (DGC) and found to stabilize striated muscle membranes. Genetic variants in the SSPN gene have been linked to development of multiple cardiovascular diseases including cardiometabolic syndrome and dilated cardiomyopathy. Ex vivo analysis of Langendorff perfused mouse hearts lacking SSPN indicates that they have increased susceptibility to ischemia/reperfusion injury after exposure to cigarette smoke (CSE). Previous studies from our laboratory showed that SSPN-deficiency decreases the heart’s ability to buffer oxidative stress after ischemia/reperfusion (I/R) injury and CSE. In addition, SSPN-deficient mice have increased pro-inflammatory signatures in adipose and other tissues in response to obesogenic conditions and smoking may heighten that risk. Therefore, we hypothesize that genetic variants in the SSPN locus may interfere with normal oxidative stress buffering conditions rendering the myocardium more susceptible to oxidative stress that occurs during I/R and CSE. Methods: To assess the impact of diminished SSPN expression, two-month-old global SSPN-/- and WT C57BL/6J mice were first subjected to either control or high fat diet conditions (60% fat) for one months for one month prior to exposure to cigarette smoke (CSE) or room air. Since CSE and obesity-promoting conditions increase oxidative stress, we examined the hearts of SSPN-deficient mice shown to have increased pro-inflammatory pathway activation. After exposure of SSPN-deficient and control mice to CSE or room air (RA) and either control or high fat diet the mice were evaluated by EchoMRI, glucose tolerance testing, echocardiography, and histological methods. Results: Preliminary findings indicate that ex vivo SSPN-/- hearts from CSE exposed mice exposed have larger areas of myocardial damage indicated by CSE tetrazolium tetrachloride (TTC)-staining. SSPN-deficiency was protective against weight gain in female HFD CSE SSPN-/- mice compared to WT females under the same conditions. Sex differences were observed with the HFD SSPN-/- female mice exhibiting decreased glucose tolerance under both RA and CSE conditions. Conversely WT females showed a synergistic decline in glucose tolerance when both HFD and CSE conditions were present. After exposure to CSE both WT male and female mice showed significant increases in body weight and fat % in response to HFD, while neither SSPN-/- male or females exhibited differences. Conclusions: SSPN-deficiency increases susceptibility to cardiac injury in mice subjected to CSE and increases glucose intolerance even while protecting against weight gain. These findings suggest that increased oxidative stress and activation of specific immune signaling pathways are contributing factors. Funding Sources: Florida Department of Health, James and Esther King #21K12 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.