The PKD inhibitor CID755673 enhances heart function in diabetic db/db mice

Diabetic cardiomyopathy is a key contributor to heart failure and mortality in T2D. As current anti-diabetic drugs have little impact on the development of diabetic cardiomyopathy, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD). PKD has previously shown to be activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We hypothesised that PKD inhibition would protect from the development of diabetic cardiomyopathy. We tested this hypothesis in the obese and T2D model, db/db mouse, with the use of a selective PKD inhibitor CID755673. We first determined the level of cardiac PKD activity in the obese and T2D db/db mouse and validated its use as a model of early stage diabetic cardiomyopathy. T2D db/db mice exhibited a 2-fold increase in cardiac PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. This increased PKD activity was associated with both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. Chronic administration CID755673 to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight and cardiomyocyte cell size. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition may provide an effective strategy to enhance heart function in obese and T2D patients.