Background-The inhibition of dipeptidyl peptidase-4 (DPP4) protects the heart from acute myocardial ischemia.However, the role of DPP4 in chronic heart failure independent of coronary artery disease remains unclear. Methods and Results-We first localized the membrane-bound form of DPP4 to the capillary endothelia of rat and human heart tissue. Diabetes mellitus promoted the activation of the membrane-bound form of DPP4, leading to reduced myocardial stromal cell-derived factor-1␣ concentrations and resultant angiogenic impairment in rats. The diabetic rats exhibited diastolic left ventricular dysfunction (DHF) with enhanced interstitial fibrosis caused partly by the increased ratio of matrix metalloproteinase-2 to tissue inhibitor of metalloproteinase-2 in a DPP4-dependent fashion. Both genetic and pharmacological DPP4 suppression reversed the stromal cell-derived factor-1␣-dependent microvasculopathy and DHF associated with diabetes mellitus. Pressure overload induced DHF, which was reversed by DPP4 inhibition via a glucagon-like peptide-1/cAMP-dependent mechanism distinct from that for diabetic heart. In patients with DHF, the circulating DPP4 activity in peripheral veins was associated with that in coronary sinus and with E/eЈ, an echocardiographic parameter representing DHF. Comorbid diabetes mellitus increased the circulating DPP4 activities in both peripheral veins and coronary sinus. Conclusions-DPP4 inhibition reverses DHF via membrane-bound DPP4/stromal cell-derived factor-1␣-dependent local actions on angiogenesis and circulating DPP4/glucagon-like peptide-1-mediated inotropic actions. Myocardium-derived DPP4 activity in coronary sinus can be monitored by peripheral vein sampling, which partly correlates with DHF index; thus, circulating DPP4 may potentially serve as a biomarker for monitoring DHF. (Circulation. 2012;126:1838-1851.)Key Words: angiogenesis Ⅲ diabetes mellitus Ⅲ dipeptidyl peptidase 4 Ⅲ glucagon-like peptide 1 Ⅲ heart failure Ⅲ microcirculation D ipeptidyl peptidase-4 (DPP4), also known as cellsurface antigen CD26, is a 110-kDa type II integral membrane glycoprotein that exhibits protease activity and belongs to the prolyl oligopeptidase family. [1][2][3] A primary function of DPP4 is to truncate various bioactive molecules such as stromal cell-derived factor-1␣ (SDF-1␣) and glucagon-like peptide-1 (GLP-1), and several reports have suggested that DPP4 represents a subfamily of gelatinolytic serine proteases that selectively bind to denatured collagen 4,5 ; hence, DPP4 modulates pathological conditions such as diabetes mellitus (DM), malignancy, and inflammation. DPP4 is widely distributed in mammalian tissues, including kidney, small intestine, liver, and heart tissues. 2 A soluble form of DPP4 (s-DPP4), present in the circulatory system and body fluids, is thought to result from the proteolytic cleavage of the membrane-bound form (m-DPP4). 3 The results of an early study using colorimetric enzyme histochemistry suggested that the DPP4 protease activity is localized in the venous capill...

Aims/hypothesis Resistin is a cytokine derived from adipose tissue and is implicated in obesity-related insulin resistance and type 2 diabetes mellitus. Polymorphisms of the resistin gene (RETN) have been shown to affect the plasma resistin concentration. The aims of this study were to identify polymorphisms of RETN that influence plasma resistin concentration and to clarify the relation between plasma resistin level and metabolic disorders in an aged Japanese cohort. Methods The study participants comprised 3133 individuals recruited to a population-based prospective cohort study (KING study). Plasma resistin concentration, BMI, abdominal circumference, blood pressure, fasting plasma glucose and serum insulin concentrations, HbA 1c content and serum lipid profile were measured in all participants. The HOMA index of insulin resistance (HOMA-IR) was also calculated. Eleven polymorphisms of RETN were genotyped. Results A combination of ANOVA and multiple linear regression analysis in screening and large-scale subsets of the study population revealed that plasma resistin concentration was significantly associated with rs34861192 and rs3745368 polymorphisms of RETN. Multiple linear regression analysis with adjustment for age and sex also showed that the plasma resistin level was significantly associated with serum concentrations of HDL-cholesterol, triacylglycerol and insulin, as well as with BMI. Conclusions/interpretation Our results implicate the rs34861192 and rs3745368 polymorphisms of RETN as robust and independent determinants of plasma resistin concentration in the study population. In addition, plasma resistin level was associated with dyslipidaemia, serum insulin concentration and obesity.

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Genotyping of these polymorphisms may prove informative for assessment of the genetic risk of CAD in low- or high-risk men or women.

Mitochondria showed functional impairment and morphological disorganization in the left ventricle of HCM patients without baseline systolic dysfunction. These mitochondrial changes were associated with impaired myocardial contractile and relaxation reserves.