The Dipeptidyl Peptidase-4 Substrate CXCL12 has Opposing Cardiac Effects in Young Mice and Aged Diabetic Mice Mediated By Ca 2+ Flux and Phosphoinositide 3-Kinase γ

Blood glucose lowering therapies can positively or negatively affect heart function in Type 2 diabetes, or they can have neutral effects. Dipeptidyl peptidase-4 (DPP-4) inhibitors lower blood glucose by preventing the proteolytic inactivation of glucagon-like peptide-1 (GLP-1). However, GLP-1 is not the only peptide substrate of DPP-4. Here, we investigated the GLP-1 independent cardiac effects of DPP-4 substrates. Pointing to GLP-1 receptor (GLP-1R) independent actions, DPP-4 inhibition prevented systolic dysfunction equally in pressure overloaded wildtype and GLP-1R knockout mice. Likewise, DPP-4 inhibition or the DPP-4 substrates, substance P or CXCL12 improved contractile recovery following no-flow ischemia in the hearts of otherwise healthy young adult mice. Either DPP-4 inhibition or CXCL12 increased phosphorylation of the Ca2+ regulatory protein, phospholamban and CXCL12 directly enhanced cardiomyocyte Ca2+ flux. In contrast, hearts of aged, obese diabetic mice (which may better mimic the comorbid patient population) had diminished levels of phospholamban phosphorylation. In this setting, CXCL12 paradoxically impaired cardiac contractility in a phosphoinositide 3-kinase γ dependent manner. These findings indicate that the cardiac effects of DPP-4 inhibition primarily occur through GLP-1R independent processes and that ostensibly beneficial DPP-4 substrates can paradoxically worsen heart function in the presence of comorbid diabetes.