Introduction: Diabetes is associated with an increased risk of heart failure even in the absence of coronary artery disease or hypertension, suggesting direct pathological effects on the myocardium. Cardiac lipotoxicity, a feature of diabetes, promotes myocardial inflammation, apoptosis and mitochondrial dysfunction, leading to fibrosis and hypertrophy, and ultimately, cardiac dysfunction. Moreover, it promotes defective insulin signalling and enhanced utilisation of lipids over glucose for ATP production. This has significant implications during ischaemia. Thus, prevention of lipotoxicity provides an attractive therapeutic strategy with implications for cardiomyopathy and myocardial infarction. The E3 ligase, inducible degrader of the LDL receptor (IDOL), is associated with reduced lipid accumulation in vivo. It also targets the VLDL receptor, which is linked to increased survival following a myocardial infarction.
Methods/Results: Cardiac IDOL-AAV induction in db/db mice was associated with a significant attenuation of diabetes-associated accumulation of cardiac lipids including triglycerides and diacylglycerides. A concomitant reduction in markers of key pathways linked to diabetic cardiomyopathy were observed, including ER stress (CHOP), inflammation (TNFa, MCP-1, IL-10) and fibrosis (procollagen III). Importantly, these effects were observed in the absence of an elevation in plasma triglyceride levels.
IDOL adenoviral induction in mouse primary cardiomyocytes was associated with enhanced insulin-stimulated Akt phosphorylation. Given the importance of glucose handling in the setting of hypoxia, we subsequently assessed whether IDOL-AAV treated mice would be protected from myocardial ischaemia-reperfusion injury. 60 minutes of cardiac ischaemia followed by 24 hours reperfusion was associated with a significant elevation of inflammatory markers in chow and high fat diet fed mice. Indeed, IDOL-AAV was associated with a marked attenuation of cardiac TNFa expression in chow and high fat diet fed mice and almost completely normalized iNOS expression.
These studies provide the first evidence of a cardioprotective role of IDOL in the setting of diabetic cardiomyopathy and ischaemia-reperfusion injury.