Set7 Deletion Prevents Glucose Intolerance and Improves the Recovery of Cardiac Function After Ischemia and Reperfusion in Obese Female Mice

Abstract

Background/Aims: An obesogenic diet (high fat and sugar, low fiber) is associated with an increased risk for metabolic and cardiovascular disorders. Previous studies have demonstrated that epigenetic changes can modify gene transcription and protein function, playing a key role in the development of several diseases. The methyltransferase Set7 methylates histone and non-histone proteins, influencing diverse biological and pathological processes. However, the functional role of Set7 in obesity-associated metabolic and cardiovascular complications is unknown. Methods: Wild type and Set7 knockout female mice were fed a normal diet or an obesogenic diet for 12 weeks. Body weight gain and glucose tolerance were measured. The 3T3-L1 cells were used to determine the role of Set7 in white adipogenic differentiation. Cardiac morphology and function were evaluated by histology and echocardiography. An ex vivo Langendorff perfusion system was used to model cardiac ischemia/reperfusion (I/R). Results: Here, we report that Set7 protein levels were enhanced in the heart and perigonadal adipose tissue (PAT) of female mice fed an obesogenic diet. Significantly, loss of Set7 prevented obesogenic diet-induced glucose intolerance in female mice although it did not affect the obesogenic diet-induced increase in body weight gain and adiposity in these animals, nor did Set7 inhibition change white adipogenic differentiation in vitro. In addition, loss of Set7 prevented the compromised cardiac functional recovery following ischemia and reperfusion (I/R) injury in obesogenic diet-fed female mice; however, deletion of Set7 did not influence obesogenic diet-induced cardiac hypertrophy nor the hemodynamic and echocardiographic parameters. Conclusion: These data indicate that Set7 plays a key role in obesogenic diet-induced glucose intolerance and compromised myocardial functional recovery after I/R in obese female mice.

Set7 deletion attenuates isoproterenol-induced cardiac fibrosis and delays cardiac dysfunction

“…Since Set7 is critical for calcium handling in cardiomyocytes and loss of Set7 affects cardiomyocyte contractile activity [42], it is possible that prolonged exposure to isoproterenol might impact calcium transients and myocardial function. Recently, we demonstrated that loss of Set7 improves the recovery of cardiac function after I/R injury in obese female mice [22]. Therefore, our results indicate that Set7 plays a key role in cardiac dysfunction in response to different stimuli.…”

“…In addition, streptozotocin-induced type 1 diabetic rats exhibit higher Set7 protein levels in the heart [21]. Recently, we also identified that Set7 protein levels are increased in the hearts of obese female mice [22]. Together, these studies suggest that Set7 may influence cardiac morphology and function.…”

“…In addition, Set7 protein levels are increased in diabetic cardiomyopathy induced by streptozotocin [21]. Recently, we identified that obese female mice had an increase in cardiac Set7 protein levels and Set7 deletion improved cardiac functional recovery after ischemia-reperfusion (I/R) injury [22], suggesting that Set7 may exert an important role in the regulation of cardiac function.…”