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Insulin sensitizers, while effective in glucose-lowering for diabetes control, are linked to an increased risk of heart disease through mechanisms that are not well understood. In this study, we investigated the molecular mechanisms underlying the effects of insulin sensitization on cardiac sinus node dysfunction. We used pharmacologic or genetic approaches to enhance insulin sensitivity, by treating with pioglitazone or rosiglitazone, or through phosphatase and tensin homolog (PTEN) deletion in cardiomyocytes respectively. We employed an angiotensin II (Ang II)-induced hypertensive animal model which causes sinus node dysfunction and accumulation of oxidized calcium/calmodulin-dependent protein kinase II (CaMKII), which also serves as a biomarker for this defect. While neither PTEN deficiency nor insulin sensitizers caused sinus node dysfunction in normotensive mice, both accelerated the onset of sinus node dysfunction and CaMKII oxidation in hypertensive mice. These abnormalities were accompanied by a significant defect in autophagy as revealed by unc-51 like autophagy activating kinase 1 (ULK1) signaling. Indeed, mice deficient in ulk1 in cardiomyocytes and the sinus node also showed early onset of slow atrial impulse conduction with frequent sinus pauses and upregulated CaMKII oxidation following Ang II infusion similar to that seen with PTEN deficiency, or treatment with insulin sensitizers. To further elucidate the role of autophagy in sinus node dysfunction, we treated mice with a peptide D-Tat-beclin1 that enhanced autophagy, which significantly abrogated the frequent sinus pauses and accumulation of oxidized CaMKII induced by insulin sensitizers treatment, or PTEN deficiency in hypertensive animals. Together, these findings provide clear evidence of the detrimental cardiac effects of insulin sensitization that occurs through failure of autophagy-mediated proteolytic clearance. [ABSTRACT FROM AUTHOR]

Aims Autophagy is essential to maintain tissue homeostasis, particularly in long-lived cells such as cardiomyocytes. Whereas many studies support the importance of autophagy in the mechanisms underlying obesity-related cardiac dysfunction, the role of autophagy in cardiac lipid metabolism remains unclear. In the heart, lipotoxicity is exacerbated by cardiac lipoprotein lipase (LPL), which mediates accumulation of fatty acids to the heart through intravascular triglyceride (TG) hydrolysis. Methods and results In both genetic and dietary models of obesity, we observed a substantial increase in cardiac LPL protein levels without any change in messenger ribonucleic acid (mRNA). This was accompanied by a dramatic down-regulation of autophagy in the heart, as revealed by reduced levels of unc-51 like kinase-1 (ULK1) protein. To further explore the relationship between cardiac LPL and autophagy, we generated cardiomyocyte-specific knockout mice for ulk1 (Myh6-cre/ulk1fl/fl), Lpl (Myh6-cre/Lplfl/fl), and mice with a combined deficiency (Myh6-cre/ulk1fl/fl Lplfl/fl). Similar to genetic and dietary models of obesity, Myh6-cre/ulk1fl/fl mice had a substantial increase in cardiac LPL levels. When these mice were fed a high-fat diet (HFD), they showed elevated cardiac TG levels and deterioration in heart function. However, with combined deletion of LPL and ULK1 in Myh6-cre/ulk1fl/fl Lplfl/fl mice, HFD feeding did not lead to alterations in levels of TG or diacylglycerol, or in cardiac function. To further elucidate the role of autophagy in cardiac lipid metabolism, we infused a peptide that enhanced autophagy (D-Tat-beclin1). This effectively lowered LPL levels at the coronary lumen by restoring autophagy in the genetic model of obesity. This decrease in cardiac luminal LPL was associated with a reduction in TG levels and recovery of cardiac function. Conclusion These results provide clear evidence of the critical role of modulating cardiac LPL activity through autophagy-mediated proteolytic clearance as a potential novel strategy to overcome obesity-related cardiomyopathy. [ABSTRACT FROM AUTHOR]