This Article Full Text Full Text (PDF) Data Supplement Correction (v118,pe81) All Versions of this Article: 117/18/2340    most recent CIRCULATIONAHA.107.739938v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Ban, K. Articles by Husain, M. PubMed PubMed Citation Articles by Ban, K. Articles by Husain, M. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Nucleotide Protein UniGene Compound via MeSH Substance via MeSH Related Collections Autonomic, reflex, and neurohumoral control of circulation Other Vascular biology Cell signalling/signal transduction Genetically altered mice Related Article

(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.

---

 

CLINICAL PERSPECTIVE

Related Article:

Clinical Summaries
Circulation 2008 117: 2309-2310. [Full Text]