Ceramide‐induced Mitochondrial Fission is Necessary for Sidestream Cigarette Smoke‐induced Cardiometabolic Disruption

Abstract

Primary and secondary smoke exposure occupy two of the top ten causes of preventable deaths, largely due to increased cardiovascular mortality. Additionally, cigarette smoking reduces insulin sensitivity, which further increases the risk of smoke-related comorbidities. The purpose of these studies was to determine the mediating mechanism whereby sidestream smoke exacerbates myocardial and skeletal muscle mitochondrial respiration and whole-body insulin resistance. Mice were fed a standard diet (SD) or high-fat, high-sugar diet (HFHS) for 12 wk while receiving daily exposure to sidestream smoke (SS) with or without myriocin IP injection. We found that ceramides were dramatically upregulated in the heart and less so in soleus with SS with little or no increase when combined with HFHS diet. While myriocin was sufficient to prevent the increase in heart and soleus ceramides with SS or HFHS diet alone, combined SS+HFHS diet was sufficiently robust to overcome the protective effect of myriocin. As predicted, mitochondrial respiration in permeabilized myocardium and red gastrocnemius was reduced with SS and SS+HFHS diet and myriocin generally restored respiration. Similar trends were observed with insulin resistance (via HOMA-IR). We suspect that reduced mitochondrial respiration with ceramide accrual is a consequence of ceramide-induced mitochondrial fission; when fission was prevented with DRP1 inhibition, mitochondrial respiration and insulin signaling was maintained despite ceramide accrual. Altogether, these findings suggest ceramide accrual and subsequent mitochondrial fission is required for the cardiometabolic consequences of sidestream cigarette smoke exposure.