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...

Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T. Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol Heart Circ Physiol 305: H295-H304, 2013. First published May 24, 2013 doi:10.1152/ajpheart.00990.2012.-Glucagonlike peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) is a remedy for type 2 diabetes mellitus (T2DM). Ex-4 ameliorates cardiac dysfunction induced by myocardial infarction in preclinical and clinical settings. However, it remains unclear whether Ex-4 may modulate diabetic cardiomyopathy. We tested the impact of Ex-4 on two types of diabetic cardiomyopathy models, genetic (KK) and acquired T2DM induced by high-fat diet [diet-induced obesity (DIO)], to clarify whether Ex-4 may combat independently of etiology. Each type of mice was divided into Ex-4 (24 nmol·kg Ϫ1 ·day Ϫ1 for 40 days; KK-ex4 and DIO-ex4) and vehicle (KK-v and DIO-v) groups. Ex-4 ameliorated systemic and cardiac insulin resistance and dyslipidemia in both T2DM models. T2DM mice exhibited systolic (DIO-v) and diastolic (DIO-v and KK-v) left ventricular dysfunctions, which were restored by Ex-4 with reduction in left ventricular hypertrophy. DIO-v and KK-v exhibited increased myocardial fibrosis and steatosis (lipid accumulation), in which were observed cardiac mitochondrial remodeling and enhanced mitochondrial oxidative damage. Ex-4 treatment reversed these cardiac remodeling and oxidative stress. Cytokine array revealed that Ex-4-sensitive inflammatory cytokines were ICAM-1 and macrophage colony-stimulating factor. Ex-4 ameliorated myocardial oxidative stress via suppression of NADPH oxidase 4 with concomitant elevation of antioxidants (SOD-1 and glutathione peroxidase). In conclusion, GLP-1R agonism reverses cardiac remodeling and dysfunction observed in T2DM via normalizing imbalance of lipid metabolism and related inflammation/oxidative stress.

In the peripheral blood leukocytes (PBLs) from the carriers of the human T-lymphotropic virus type-1 (HTLV-1) or the patients with adult T-cell leukemia (ATL), nuclear factor kappaB (NF-κB)-mediated antiapoptotic signals are constitutively activated primarily by the HTLV-1-encoded oncoprotein Tax. Tax interacts with the I κB kinase regulatory subunit NEMO (NF-κB essential modulator) to activate NF-κB, and this interaction is maintained in part by a molecular chaperone, heat-shock protein 90 (HSP90), and its co-chaperone cell division cycle 37 (CDC37). The antibiotic geldanamycin (GA) inhibits HSP90's ATP binding for its proper interaction with client proteins. Administration of a novel water-soluble and less toxic GA derivative, 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride (17-DMAG), to Tax-expressing ATL-transformed cell lines, C8166 and MT4, induced significant degradation of Tax. 17-DMAG also facilitated growth arrest and cellular apoptosis to C8166 and MT4 and other ATL cell lines, although this treatment has no apparent effects on normal PBLs. 17-DMAG also downregulated Tax-mediated intracellular signals including the activation of NF-κB, activator protein 1 or HTLV-1 long terminal repeat in Tax-transfected HEK293 cells. Oral administration of 17-DMAG to ATL model mice xenografted with lymphomatous transgenic Lck-Tax (Lck proximal promoter-driven Tax transgene) cells or HTLV-1-producing tumor cells dramatically attenuated aggressive infiltration into multiple organs, inhibited de novo viral production and improved survival period. These observations identified 17-DMAG as a promising candidate for the prevention of ATL progression.

Aim: Cerebral white matter lesions (WML) are known to increase with age, as is left ventricular (LV) diastolic dysfunction with normal contraction. Although aging is a common risk factor, the link between these diseases is not fully understood. The aim was to clarify this relationship, using the ratio between early diastolic mitral inflow and early diastolic mitral annular tissue velocity (E/E'). E/E' measured by tissue Doppler echocardiography offers an indicator of the severity of LV diastolic dysfunction, reflecting both diastolic LV stiffness and diastolic LV filling pressure. Methods:Participants comprised 75 patients aged between 65 and 75 years with normal LV contraction and no signs or history of symptomatic heart failure, ischemic heart diseases, atrial fibrillation, stroke, or cognitive dysfunction. The volume of WML was quantified on brain magnetic resonance imaging. Results:The participants were classified into three groups: Low E/E', E/E' ≤ 8; Middle E/E', 8 < E/E' < 15; and High E/E', E/E' ≥ 15. WML volume was 3.6 ± 3.0 mL in Low E/E', 5.4 ± 6.5 mL in Middle E/E' and 12.0 ± 11.0 mL in High E/E', increasing significantly with increased diastolic LV stiffness (Low vs High, P = 0.034; Middle vs High, P = 0.016). Linear regression analysis showed the positive association between the volume of WML and E/E' ratio (r = 0.377, P = 0.0009). Conclusions:This investigation identified an association between LV diastolic dysfunction and WML. Further investigations are required to clarify whether there is a direct association between the two diseases. Geriatr Gerontol Int 2014; 14 (Suppl. 2): 71-76.Keywords: cerebral white matter lesions, left ventricular diastolic dysfunction, ratio of early diastolic mitral inflow to early diastolic mitral annular tissue velocity.