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(Circulation. 2008;117:2340-2350.)
© 2008 American Heart Association, Inc.

Molecular Cardiology

Cardioprotective and Vasodilatory Actions of Glucagon-Like Peptide 1 Receptor Are Mediated Through Both Glucagon-Like Peptide 1 Receptor–Dependent and –Independent Pathways

Kiwon Ban, MSc; M. Hossein Noyan-Ashraf, PhD; Judith Hoefer, MD; Steffen-Sebastian Bolz, MD, PhD; Daniel J. Drucker, MD^*; Mansoor Husain, MD^*

From the Heart and Stroke Richard Lewar Centre of Excellence for Cardiovascular Research (K.B., M.H.N.-A., J.H., S.-S.B., M.H.), Department of Medicine (D.J.D., M.H.), Institute of Medical Science (J.H., D.J.D., M.H.), Department of Physiology (K.B., S.-S.B.), and Banting and Best Diabetes Centre (D.J.D.), University of Toronto; Samuel Lunenfeld Research Institute, Mount Sinai Hospital (D.J.D.); and Toronto General Hospital Research Institute, Toronto General Hospital (K.B., M.H.N.-A., J.H., M.H.), Toronto, Ontario, Canada.

Correspondence to Mansoor Husain, MD, Toronto General Hospital Research Institute, 200 Elizabeth St, TMDT3-909, Toronto, Ontario, Canada M5G-1C4. E-mail mansoor.husain{at}utoronto.ca

Received September 13, 2007; accepted February 29, 2008.

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.

Methods and 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.

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