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 ischemiareperfusion injury of isolated hearts and dilated preconstricted arteries from wild-type mice. Unexpectedly, many of these actions of GLP-1 were preserved in Glp1r Ϫ/Ϫ 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 Ϫ/Ϫ 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.

Key Words: myogenic response Ⅲ heart failure Ⅲ sphingosine-1-phosphate Ⅲ mitogen-activated protein kinase H eart failure (HF) is a progressive condition that affects more than 2% of the population and accounts for Ϸ$28 billion in health care costs in the United States. 1 The prevalence of HF is increasing worldwide, and given its adverse impacts on the quality and longevity of life, 1 the burdens imposed by HF are enormous. Irrespective of etiology, HF presents as a clinical syndrome of reduced cardiac output and or elevated cardiac filling pressures. [2][3][4] In the former, cardiac-renal-hormonal axes and sympathetic neural reflexes are activated in an attempt to maintain sufficient mean arterial pressure (MAP) for vital organ perfusion. 4 This is achieved through increased salt and water retention 4 (ultimately worsening the deleterious volume overload of HF), and through an increase in peripheral resistance (PR). 5 Although increased PR may support MAP in certain circumstances, chronic elevations in PR contribute to a pressure afterload that further limits cardiac output in HF, 3 and drives adverse cardiac remodeling. 3 Such "vicious cycles" are believed to play a key role in the progressive nature of HF, and many advances in its management have been aimed at Original received August 5, 2009; resubmission received June 18, 2010; revised resubmission received July 19, 2010; accepted July 20, 2010. In June 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days.From mitigating this pathophysiology. In general, increased PR in HF is thought to be conveyed by neurohumoral activation, including the sympathetic nervous system, 6 the renin-angiotensin system (RAS), 4 and local mechanisms such as the myogenic response. 7 Our present purpose was to investigate the molecular mechanisms that underlie the latter, ie, myogenic elevations of PR in HF, to identify potentially novel therapeutic targets. Indeed, growing evidence suggests that long-term elevations in PR depend more on "local" vascular mechanisms than systemic factors such as the sympathetic activation of orthostasis. 5 Moreover, reasons why chronic maintenance of high PR in HF by systemic sympathetic (ie, ␣ 1 -adrenergic) enhancement of peripheral vasoconstriction 2,8 is disadvantageous include: (1) increased sympathetic output compromises a failing myocardium (via tachycardia, arrhythmia, cytotoxicity 9 ); and (2) catecholamine potency diminishes because of adrenergic receptor desensitization. 10 -12 We thus posited that distinct local mechanisms would participate in chronic elevations in PR observed in HF. Supporting this premise, the maintenance of peripheral vascular tone largely depends on "myogenic" mechanisms intrinsic to vascular smooth muscle cells (VSMCs). 13 On a local level, myogenic mechanisms serve to adapt vascular tone to changes in transmural pressure. Systemically, myogenic vasoconstriction can amplify vasopressor responses by positive feedback on systemic blo...