Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways.
BACKGROUND
The glucagon-like peptide 1 receptor (GLP-1R) is believed to mediate glucoregulatory and cardiovascular effects of the incretin hormone GLP-1(7-36) (GLP-1), which is rapidly degraded by dipeptidyl peptidase-4 (DPP-4) to GLP-1(9-36), a truncated metabolite generally thought to be inactive. Novel drugs for the treatment of diabetes include analogues of GLP-1 and inhibitors of DPP-4; however, the cardiovascular effects of distinct GLP-1 peptides have received limited attention.


RESULTS
Here, we show that endothelium and cardiac and vascular myocytes express a functional GLP-1R as GLP-1 administration increased glucose uptake, cAMP and cGMP release, left ventricular developed pressure, and coronary flow in isolated mouse hearts. GLP-1 also increased functional recovery and cardiomyocyte viability after ischemia-reperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r(-/-) mice. Furthermore, GLP-1(9-36) administration during reperfusion reduced ischemic damage after ischemia-reperfusion and increased cGMP release, vasodilatation, and coronary flow in wild-type and Glp1r(-/-) mice, with modest effects on glucose uptake. Studies using a DPP-4-resistant GLP-1R agonist and inhibitors of DPP-4 and nitric oxide synthase showed that the effects of GLP-1(7-36) were partly mediated by GLP-1(9-36) through a nitric oxide synthase-requiring mechanism that is independent of the known GLP-1R.


CONCLUSIONS
These data describe cardioprotective actions of GLP-1(7-36) mediated through the known GLP-1R and novel cardiac and vascular actions of GLP-1(7-36) and its metabolite GLP-1(9-36) independent of the known GLP-1R. Our data suggest that the extent to which GLP-1 is metabolized to GLP-1(9-36) may have functional implications in the cardiovascular system.
Ban
Kiwon
K
Heart and Stroke Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Ontario, Canada M5G-1C4.
Noyan-Ashraf
M Hossein
MH
Hoefer
Judith
J
Bolz
Steffen-Sebastian
SS
Drucker
Daniel J
DJ
Husain
Mansoor
M
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D000067757:Glucagon-Like Peptide-1 Receptor; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017202:Myocardial Ischemia / Q000503:physiopathology* / Q000517:prevention & control*; D010446:Peptide Fragments / Q000502:physiology; D051381:Rats; D018027:Receptors, Glucagon / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D014664:Vasodilation / Q000235:genetics / Q000502:physiology*
C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1