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 gamma

Author(s):Show less -

Batchu, Sri N. ^{[1, 2]} ; Thieme, Karina ^{[3, 1, 2]} ; Zadeh, Farigol H. ^{[4, 5]} ; Alghamdi, Tamadher A. ^{[1, 2]} ; Yerra, Veera Ganesh ^{[1, 2]} ; Hadden, Mitchell J. ^{[1, 2]} ; Majumder, Syamantak ^{[1, 2, 6]} ; Kabir, M. Golam ^{[1, 2]} ; Bowskill, Bridgit B. ^{[1, 2]} ; Ladha, Danyal ^{[1, 2]} ; Gramolini, Anthony O. ^{[4, 5]} ; Connelly, Kim A. ^{[4, 1, 2]} ; Advani, Andrew ^{[1, 2]}

Affiliation

^[1] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON - Canada

^[2] St Michaels Hosp, Keenan Res Ctr Biomed Sci, Toronto, ON - Canada

^[3] Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Sao Paulo - Brazil

^[4] Univ Toronto, Dept Physiol, Toronto, ON - Canada

^[5] Univ Toronto, Ted Rogers Ctr Heart Res, Toronto, ON - Canada

^[6] Birla Inst Technol & Sci, Dept Biol Sci, Pilani, Rajasthan - India

• Document type: Journal article
• Source: Diabetes; v. 67, n. 11, p. 2443-2455, NOV 2018.
• Web of Science Citations: 2

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 gamma-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. (AU)

• FAPESP's process: 16/04591-1 - Non-coding RNAs in diabetic kidney disease
• Grantee: Karina Thieme
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor