PMID- 30150305
OWN - NLM
STAT- MEDLINE
DCOM- 20181224
LR  - 20181224
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Linking)
VI  - 67
IP  - 11
DP  - 2018 Nov
TI  - 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 
      gamma.
PG  - 2443-2455
LID - 10.2337/db18-0410 [doi]
AB  - 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 Ca(2+) regulatory protein phospholamban (PLN), and CXCL12 
      directly enhanced cardiomyocyte Ca(2+) 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.
CI  - (c) 2018 by the American Diabetes Association.
FAU - Batchu, Sri N
AU  - Batchu SN
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Thieme, Karina
AU  - Thieme K
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Zadeh, Farigol H
AU  - Zadeh FH
AD  - Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
AD  - Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, 
      Canada.
FAU - Alghamdi, Tamadher A
AU  - Alghamdi TA
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Yerra, Veera Ganesh
AU  - Yerra VG
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Hadden, Mitchell J
AU  - Hadden MJ
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Majumder, Syamantak
AU  - Majumder S
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Kabir, M Golam
AU  - Kabir MG
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Bowskill, Bridgit B
AU  - Bowskill BB
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Ladha, Danyal
AU  - Ladha D
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
FAU - Gramolini, Anthony O
AU  - Gramolini AO
AD  - Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
AD  - Ted Rogers Centre for Heart Research, University of Toronto, Toronto, Ontario, 
      Canada.
FAU - Connelly, Kim A
AU  - Connelly KA
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
AD  - Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
FAU - Advani, Andrew
AU  - Advani A
AUID- ORCID: 0000-0003-0497-645X
AD  - Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge 
      Institute, St. Michael's Hospital, Toronto, Ontario, Canada advania@smh.ca.
LA  - eng
GR  - CIHR/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180827
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Chemokine CXCL12)
RN  - 0 (Glp1r protein, mouse)
RN  - 0 (Glucagon-Like Peptide-1 Receptor)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Animals
MH  - Calcium/*metabolism
MH  - Chemokine CXCL12/genetics/*metabolism
MH  - Diabetes Mellitus/*metabolism/physiopathology
MH  - Diet, High-Fat
MH  - Glucagon-Like Peptide-1 Receptor/genetics/metabolism
MH  - Heart/*physiopathology
MH  - Mice
MH  - Mice, Knockout
MH  - Myocardium/*metabolism
MH  - Myocytes, Cardiac/*metabolism
MH  - Phosphatidylinositol 3-Kinases/*metabolism
MH  - Phosphorylation
EDAT- 2018/08/29 06:00
MHDA- 2018/12/26 06:00
CRDT- 2018/08/29 06:00
PHST- 2018/04/13 00:00 [received]
PHST- 2018/08/14 00:00 [accepted]
PHST- 2018/08/29 06:00 [pubmed]
PHST- 2018/12/26 06:00 [medline]
PHST- 2018/08/29 06:00 [entrez]
AID - db18-0410 [pii]
AID - 10.2337/db18-0410 [doi]
PST - ppublish
SO  - Diabetes. 2018 Nov;67(11):2443-2455. doi: 10.2337/db18-0410. Epub 2018 Aug 27.