UC San Diego

The rise of type 2 diabetes (T2DM) increases the risk of diabetic cardiomyopathy. Worsened cardiovascular outcomes have been clinically observed in female diabetic patients; however, there is a lack of sex specific treatments for diabetes associated heart complications. Caveolins are integral membrane proteins expressed in caveolae and mitochondria that act as cellular signaling platforms to regulate stress responses. The cardiac-specific caveolin-3 overexpression (Cav3 OE) has been shown to protect the heart from morphological changes induced by stressors and preserve mitochondrial function, but this has not yet been shown in a diabetic heart. We tested the rationale that Cav3 will protect the heart from diabetes-induced metabolic injury and be especially advantageous for females. Mid-aged male and female Cav3 OE mice and transgene-negative (Tg-Neg) littermates were either injected with streptozotocin (STZ) and fed a 60% kcal high-fat diet (HFD) to induce diabetes or injected with citrate buffer and fed a 4% kcal low-fat diet for controls. STZ/HFD significantly increased weight and impaired glucose tolerance of male and female mice, with worsened glucose tolerance in males. Tg-Neg T2DM mice presented cardiac hypertrophy in males and females, mitochondrial dysfunction in females, diastolic dysfunction in males, and cardiac mitochondrial disarray in males and females. Meanwhile, Cav3 OE prevented these incidences in T2DM mice. Therefore, Cav3 may be a novel target to protect diabetic mice, especially females, from cardiac complications.