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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

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

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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]
Número total de Autores: 13
Afiliação do(s) autor(es):
[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
Número total de Afiliações: 6
Tipo de documento: Artigo Científico
Fonte: Diabetes; v. 67, n. 11, p. 2443-2455, NOV 2018.
Citações Web of Science: 2

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)

Processo FAPESP: 16/04591-1 - RNAs não codificantes na doença renal diabética
Beneficiário:Karina Thieme
Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado