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. 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.