DPP4 and the Cardiovascular System
As DPP-4 inhibitors are used to treat patients with type 2 diabetes, it is important to consider whether and how modulation of DPP-4 activity might affect the biology of the heart and blood vessels. A number of DPP-4 substrates have actions in the cardiovascular system:
Substrates of DPP-4 with activity in the cardiovascular system
Brain natriuretic peptide
Fibrinogen α-chain
Glucagon-like peptide-1
Glucagon
Insulin-like growth factor
Monocyte derived chemokine
Monocyte chemotactic protein-1
Monocyte chemotactic protein-2
Monocyte chemotactic protein-3
Neuropeptide Y
Regulated upon Activation, Normal
T-cell Expressed, and Secreted
Stromal cell-derived factor-1β
Tumor necrosis factor-α
Vasoactive intestinal polypeptide
The effects of sitagliptin on hemodynamics in human subjects with ischemic heart disease have been examined in a study of 14 patients with stable CAD subjected to dobutamine stress echocardiography (DSE). Patients were administered an oral glucose challenge, with or without a single administration of sitagliptin 100 mg. Sitagliptin-treated subjects exhibited a significant increase in ejection fraction, and enhanced LV regional wall motion, with improved contractile velocity in ischemic segments. DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients with Coronary Artery Disease Circ Cardiovasc Imaging. 2010 Jan 14. [Epub ahead of print]
Sauve et al examined the cardiovascular consequences of LAD ligation in normoglycemic Dpp4-/- mice, and in diabetic WT mice treated with sitagliptin or metformin. DPP4-/- hearts exhibited increased basal expression of cardioprotective genes and proteins and Dpp4-/- mice exhibited normal cardiac structure and function yet significantly increased survival sitagliptin on ischemic myocardium are likely to be indirect, as sitagliptin did not improve functional recovery in ischemic murine hearts studied ex vivo. Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes following myocardial infarction in mice Diabetes published ahead of print January 22, 2010, doi:10.2337/db09-0955
Ye and colleagues compared the effects of sitagliptin and pioglitazone on infarct size and signal transduction in rodent models of ischemia. Treatment of mice with sitagliptin or pioglitazone for 3 or 14 days reduced infarct size using an in vivo model of ischemia re-perfusion injury. Sitagliptin increased cardiac levels of cAMP, and infusion of the PKA inhibitor attenuate the cardioprotective actions of sitagliptin , but not pioglitazone. Pioglitazone and sitagliptin exerted different effects on cPLA2 and Cox2 activity, and both agents increased eNOS and CREB phosphorylation. Sitagliptin alone had no effect in isolated cardiomyocytes, whereas sitagliptin pkus exogenous GGLP-1 reduced cardiomyocyte injury in a cellular model of simulated ischemia-reperfusion injury The myocardial infarct size limiting effects of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA. Am J Physiol Heart Circ Physiol. 2010 Mar 5. [Epub ahead of print]
GLP-1(9-36): A DPP-4 generated metabolite and cardioactive peptide
Unexpectedly, both GLP-1 and GLP-1(9-36) amide were found to improve left ventricular functioning in dogs with pacing-induced dilated cardiomyopathy (DCM) Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol. 2005 Dec;289(6):H2401-8. DCM was induced by rapid right ventricular pacing for 28 days. Rapid pacing was suspended, and dogs either received a 48-hour iv infusion of GLP-1 (1.5 pmol/kg/min, n=9), GLP-1(9-36) (1.5 pmol/kg/min, n=7), or saline control. Both GLP-1 and GLP-1(9-36) significantly reduced LVEDP, and increased the first derivative of LV pressure. These improvements were nearly identical with each form of peptide. Both GLP-1 and GLP-1(9-36) significantly improved LV stroke volume, LVEF, and cardiac output to a comparable degree. GLP-1(9-36) also reduced ischemic damage following ischemia/reperfusion injury in the isolated mouse heart. Twenty minutes of GLP-1(9-36) (0.3 nM) treatment, administered immediately following ischemia during the reperfusion phase, significantly improved functional recovery of the left ventricle in wild-type and unexpectdely, in hearts from Glp1r-/- mice. GLP-1(9-36) (0.3 nM) also increased cGMP release measured from coronary effluent samples taken at various time points from normoxic perfused hearts of wild-type and Glp1r-/- mice. Both GLP-1 and GLP-1(9-36) induced vasodilation and significantly increased coronary flow to the same magnitude. The addition of sitagliptin (5 μM) to GLP-1-treated mesenteric arteries reduced, but did not abolish, the vasodilatory response to GLP-1. This suggests that both GLP-1 and the metabolite GLP-1(9-36) have vasodilatory actions. Consistent with this observation, both GLP-1 and GLP-1(9-36) elicited vasodilation in arteries from Glp1r-/- mice Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways Circulation. 2008 May 6;117(18):2340-50
Stromal cell-derived factor-1 (SDF-1)
SDF-1 is an endogenous DPP-4 substrate. Plasma from Dpp4-/- mice contains exclusively C-terminally truncated SDF-1, whereas SDF-1 was degraded at both the C- and N-terminus in wild-type mice Circulating CD26 is negatively associated with inflammation in human and experimental arthritis Am J Pathol. 2005 Feb;166(2):433-42 . Preclinical data indicates that SDF-1 expression is upregulated in the ischemic myocardium in mice immediately following infarction Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury Circulation. 2004 Nov 23;110(21):3300-5 , and myocardial SDF-1 gene transfer increases the mobilization and homing of stem cells toward ischemic myocardium, leading to neovascularization and enhanced post-infarction recovery in rats and mice Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy Lancet. 2003 Aug 30;362(9385):697-703 and Mobilizing of haematopoietic stem cells to ischemic myocardium by plasmid mediated stromal-cell-derived factor-1alpha (SDF-1alpha) treatment. Regul Pept. 2005 Feb 15;125(1-3):1-8
SDF-1 has been shown to protect against deterioration of cardiac function in mice after acute myocardial infarction via angiogenesis promotion Stromal cell-derived factor-1alpha is cardioprotective after myocardial infarction Circulation. 2008 Apr 29;117(17):2224-31. The essential role of SDF-1 in the recruitment of stem and progenitor cells toward the ischemic/hypoxic myocardium is through its cognate receptor, CXC chemokine receptor 4 (CXCR4). Zaruba et al. utilized a model of combined genetic or pharmacologic inhibition of DPP-4 with granulocyte- colony stimulating factor (G-CSF)-mediated stem cell mobilization after MI in mice. This approach lead to increased myocardial homing of circulating CXCR4+ stem-cells, reduced cardiac remodeling, and improved heart function and survival. Dpp4-/- mouse myocardium showed no DPP-4 activity 2 days post-MI, with low levels of DPP-4 activity in serum. Use of the DPP-4 inhibitor Diprotin-A in combination with G-CSF (100 μg/kg/day ip), lead to decreased DPP-4 activity following MI in the myocardium but not in serum of wild-type mice. Flow cytometry analyses of heart tissue 48h after MI revealed that both genetic and pharmacological inhibition of DPP-4 in combination with G-CSF resulted in significantly increased recruitment of CD45+/CD34+/c-kit+, CD45+/CD34+/Sca-1+, CD45+/CD34+/CXCR4+, and CD45+/CD34+/Flk-1+ progenitor cells as well as lin-c-kit+Sca-1+ hematopoietic stem cells into ischemic myocardium. This effect was reversed when these mice were treated with the CXCR4 antagonist AMD3100 (ip,1.25 mg/kg). Loss or inhibition of DPP-4 function in combination with G-CSF treatment reduced scar tissue and apoptosis and ameliorated thickness of the LV wall 30 days post-MI, as analyzed by histology. Finally, G-CSF administration in Dpp4-/- mice, or Diprotin-A-treated wild-type mice improved survival, as well as LVEF, cardiac output, and contractility Synergy between CD26/DPP-IV inhibition and G-CSF improves cardiac function after acute myocardial infarction Cell Stem Cell. 2009 Apr 3;4(4):313-23.
The SITAGRAMI-Trial (Safety and efficacy of SITAgliptin plus GRanulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction). Based on the results of preclinical studies, a randomized clinical trial is underway in human subjects with myocardial infarction and successful PCI who then receive a 5 day treatment of G-CSF and 28 days of sitagliptin.The primary study outcome is change in global myocardial function after 6 months, taken to be an indirect reflection of cardiac regeneration. Interim safety analysis of the first 36 patients did not raise any concerns as outlined in Safety and efficacy of SITAgliptin plus GRanulocyte-colony-stimulating factor in patients suffering from Acute Myocardial Infarction (SITAGRAMI-Trial) - Rationale, design and first interim analysis. Int J Cardiol. 2010 Jan 3. [Epub ahead of print]
BNP
BNP is a peptide hormone synthesized in the heart and is a major contributor in the regulation of cardiovascular homeostasis, mediating vasodilation, lusitropism, natriuresis, and supression of renin secretion. The physiological concentration of BNP in plasma noticeably increases in patients with cardiac overload. Therefore, BNP has largely been used in a clinical setting as a prognostic marker for patients with cardiac hypertrophy and heart failure. DPP-4 removes the two NH2-terminal amino acids of BNP to produce BNP(3-32) Dipeptidyl-peptidase IV converts intact B-type natriuretic peptide into its des-SerPro form Clin Chem. 2006 Jan;52(1):82-7. With respect to cardio-renal actions of BNP(3-32), this peptide has reduced renal actions when compared to full-length BNP, and lacks any vasodilating ability Des-serine-proline brain natriuretic peptide 3-32 in cardiorenal regulation Am J Physiol Regul Integr Comp Physiol. 2007 Feb;292(2):R897-901. The endogenous levels of BNP in Dpp4-/- mice and in mice and humans treated with a DPP-4 inhibitor are currently unknown, and the potential influence of BNP on cardiac remodeling and contractile dysfunction following MI requires further study.
Neuropeptide Y
Neuropeptide Y (NPY) is a 36 amino acid peptide, originally isolated from the porcine brain. NPY is primarily synthesized and released by neurons, and belongs to a family of neuroendocrine peptides. NPY is found colocalized with norepinephrine in all sympathetic nerves that innervate the cardiovascular system, and is the most abundant neuropeptide in the heart. Human coronary arteries in particular, are abundantly innervated with fibers containing NPY. The NPY receptor Y1 is the major vascular receptor in that it mediates vasoconstriction in small arteries of coronary and splanchnic vascular beds and arterial smooth muscle cell proliferation. In humans and animals, plasma NPY levels are increased in response to tissue injury and ischemia, and in a variety of conditions with sympathetic hyperactivity, such as hypertension and congestive heart failure.
Intact NPY(1-36) binds the Y1 receptor (Y1R ). Cleavage of NPY from a Y1R agonist to non-Y1 (a Y2/Y5 R ligand) is dependent on DPP-4 Proteolytic processing of neuropeptide Y and peptide YY by dipeptidyl peptidase IV Regul Pept. 1993 Dec 10;49(2):133-44. with NPY and DPP-4 being colocalized in blood vessels. DPP-4-cleaved NPY(3-36) is the second major circulating form of the peptide, and is capable of activation of all non-Y1 receptors, namely Y2, Y3 and Y5. These receptors are found not only in the central and peripheral nervous system , but also in blood vessels. DPP-4 conversion of NPY to NPY(3-36) is necessary for angiogenic activity, as the use of a DPP-4 neutralizing antibody resulted in the loss of NPY-mediated endothelial cell migration in an endothelial wound assay Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding Peptides. 2001 Mar;22(3):453-8.
A potential increase in circulating NPY as a result of reduced DPP-4 activity may have effects on blood pressure. Jackson et al. found that DPP-4 inhibition by sitagliptin augmented the ability of exogenous NPY(1-36) to enhance renovascular responses to angiotensin II (AngII) in kidneys from genetically hypertensive rats. Administration of Ang II (0.3 nmol/L) to isolated, perfused kidneys from adult spontaneously hypertensive rats (SHR) resulted in increased perfusion pressure, indicative of vasoconstriction, that was significantly enhanced when exogenous NPY(1-36) (6 nmol/L) was added to the perfusate. This effect was blocked when kidneys were pretreated for 20 minutes with 1 μM BIBP3226 (a highly selective Y1 receptor blocker), or the DPP-4 inhibitor sitagliptin (1 μM) Sitagliptin augments sympathetic enhancement of the renovascular effects of angiotensin II in genetic hypertension Hypertension. 2008 Jun;51(6):1637-42
Nevertheless, no problems with blood pressure have been detected in clinical trials examining the effects of DPP-4 inhibitors in diabetic subjecst. A short-term study in 19 non-diabetic, mild to moderately hypertensive patients revealed no effects of sitagliptin treatment (50 or 100 mg BID for 5 days) on 24-hour ambulatory blood pressure measurements Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008 May;48(5):592-8. The endogenous levels of NPY in Dpp4-/- mice and in mice treated with a DPP-4 inhibitor have not been reported, and the potential influence of NPY on coronary vasoconstriction is unknown.