Abstract 13772: Cardiac-Specific Over Expression of Caveolin-3 Protects from Diabetic Cardiomyopathy
Diabetes is a worldwide epidemic currently affecting 366 million people. Diabetic cardiomyopathy is evident as ventricular dysfunction without coronary artery disease or hypertension. Caveolae are invaginations of the plasma membrane, where caveolins act as scaffolding molecules for localization of receptors and signaling molecules. Overexpression of cardiac caveolin protects the heart from ischemia-reperfusion injury and pressure-overload hypertrophy. We hypothesize that cardiac-specific caveolin-3 (Cav-3) overexpression (OE) will protect the diabetic heart. Since diabetes is more prevalent in middle aged adults, 10 month old transgene negative (TGneg) or Cav-3 OE mice were given a single dose of strepotozotocin (STZ, 75mg/kg) and then placed on a high fat (60%) diet to induce Type II diabetes mellitus (T2DM). After 3 months, TGneg T2DM mice and Cav-3 OE T2DM mice showed an increase in body weight and altered glucose tolerance response, when compared to controls that did not receive STZ and were fed a normal diet. Echocardiography showed that Cav-3 OE T2DM mice had significantly blunted left ventricular hypertrophy (LV-Mass) when compared to TGneg T2DM controls (Cav-3 OE T2DM 77.89 ± 3.97, vs. TGneg T2DM 97.30 ± 5.75, p < 0.008, compared to TGneg 74.72 ± 3.72, and Cav-3 OE 71.08 ± 2.368, n=11-16, per group). Increased LV-Mass in TGneg T2DM mice was associated with decreased fractional shortening (%FS) when compared to Cav-3 OE T2DM (Tgneg T2DM 27.79±0.86 vs. Cav3 OE T2DM 39.44±0.98, p< 0.0001). Langendorff-perfused hearts (n=5 each) from controls and Cav-3 OE T2DM mice increased LV developed pressure in response to volume loading whereas this response was dramatically blunted in TGneg T2DM hearts. Cav-3 OE T2DM mitochondria showed protection from calcium swelling and reactive oxygen species generation similar to controls, when compared to TGneg T2DM mitochondria. Altered mitochondrial ultrastructure (i.e., mitochondrial swelling and clustering) was only found in TGneg T2DM hearts compared to other groups. Our data suggest that Cav-3 OE in the heart has the ability to limit injury in the setting of diabetes through regulation of mitochondrial structure and function. Cav-3 might be a novel target to reduce cardiac complications in diabetic patients.
- © 2012 by American Heart Association, Inc.