The Dipeptidyl Peptidase 4 Substrate CXCL12 Has Opposing Cardiac Effects in Young Mice and Aged Diabetic Mice Mediated by Ca2+ Flux and Phosphoinositide 3-Kinase γ

Author:

Batchu Sri N.1,Thieme Karina1,Zadeh Farigol H.23,Alghamdi Tamadher A.1,Yerra Veera Ganesh1,Hadden Mitchell J.1,Majumder Syamantak1,Kabir M. Golam1,Bowskill Bridgit B.1,Ladha Danyal1,Gramolini Anthony O.23,Connelly Kim A.12,Advani Andrew1ORCID

Affiliation:

1. Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada

2. Department of Physiology, University of Toronto, Toronto, Ontario, Canada

3. Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, Canada

Abstract

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 wild-type and GLP-1R knockout mice. Likewise, DPP-4 inhibition or the DPP-4 substrates substance P or C-X-C motif chemokine ligand 12 (CXCL12) improved contractile recovery after 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 (PLN), 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 PLN 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.

Funder

Boehringer Ingelheim

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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