Morihiko Aoyama

Dipeptidyl Peptidase-4 Modulates Left Ventricular Dysfunction in Chronic Heart Failure via Angiogenesis-Dependent and -Independent Actions

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&agr; 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&agr;–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/e′, 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&agr;–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.

Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes.

Glucagon-like 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(-1)·day(-1) 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.

Changes in cardiovascular parameters and plasma norepinephrine level in rats after chronic constriction injury on the sciatic nerve

&NA; To evaluate whether neuropathic pain affects autonomic nervous activities, we investigated daily change in cardiovascular parameters and plasma norepinephrine (NE) in free‐moving rats after chronic constriction injury (CCI) on the sciatic nerve. Arterial blood pressure (BP), heart rate (HR), and the power spectrum of pulse interval variability were analyzed. Daily change in motor activity and nociceptive behavior was also measured from some CCI rats. In others, NE from daily blood samples was quantified and spontaneous pain was evaluated by daily monitoring of foot guarding behavior. We identified three stages in the daily change of cardiovascular parameters and plasma NE level over 3 weeks following CCI. The first stage (up to 3 days after the surgery) was characterized by increased MAP and HR, especially in the daytime, even though plasma NE was unchanged and motor activity decreased. The second stage (mid first to mid second postoperative weeks) was characterized by increased daytime MAP and HR, and the animals developed punctate hyperalgesia in the affected hindpaw. An NE surge that may have been related to spontaneous pain was present 3–5 days after CCI. The third stage, which appeared after the second postoperative week, was characterized by normalized MAP and decreased HR, and increased high‐frequency (0.8–3.0 Hz) power in pulse interval variability, which is an index of cardiac parasympathetic tone. These results demonstrated that cardiovascular function was kept high through sympathetic and non‐sympathetic activity for 2 weeks after CCI, followed by a predominance of parasympathetic tone.

Artificially produced meteorological changes aggravate pain in adjuvant-induced arthritic rats.

To examine the effects of change in meteorological parameters on pain-related behaviors in a simulated arthritic condition, rats with an injection of complete Freunds adjuvant into the tibio-tarsal joint were exposed to low barometric pressure (20 mmHg below the natural atmospheric pressure) and low ambient temperature (7 degrees C lower than 22 degrees C) in a climate-controlled room. When the arthritic rats were exposed to these environments, the already increased number of hindpaw withdrawals in response to noxious mechanical stimulation (hyperalgesia) was further increased, and a hindpaw withdrawal response to innocuous mechanical stimulation (allodynia) began to occur. Such exposures did not influence any of the pain-related behaviors of the control rats. These results show that lowering barometric pressure and ambient temperature within the range of natural environmental fluctuation intensify pain in arthritic rats.

Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis

Background—Ample evidence demonstrates cardiovascular protection by incretin-based therapy using dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 (GLP-1) under either diabetic or nondiabetic condition. Their action on myocardium is mediated by the cyclic AMP (cAMP) signal; however, the pathway remains uncertain. This study was conducted to address the effect of DPP4i/GLP-1/cAMP axis on cardiac dysfunction and remodeling induced by pressure overload (thoracic aortic constriction [TAC]) independently of diabetes mellitus. Methods and Results—DPP4i (alogliptin, 10 mg/kg per day for 4 weeks) prevented TAC-induced contractile dysfunction, remodeling, and apoptosis of myocardium in a GLP-1 receptor antagonist (exendin [9-39])–sensitive fashion. In TAC, circulating level of GLP-1 (in pmol/L; 0.86±0.10 for TAC versus 2.13±0.54 for sham control) unexpectedly declined and so did the myocardial cAMP concentration (in pmol/mg protein; 33.0±1.4 for TAC versus 42.2±1.5 for sham). Alogliptin restored the decline in the GLP-1/cAMP levels observed in TAC, thereby augmented cAMP signaling effectors (protein kinase A [PKA] and exchange protein directly activated by cAMP 1 [EPAC1]). In vitro assay revealed distinct roles of PKA and EPAC1 in cardiac apoptosis. EPAC1 promoted cardiomyocyte survival via concomitant increase in B cell lymphoma-2 (Bcl-2) expression and activation of small G protein Ras-related protein 1 (Rap1) in a cAMP dose–dependent and PKA–independent fashion. Conclusions—DPP4i restores cardiac remodeling and apoptosis caused by the pathological decline in circulating GLP-1 in response to pressure overload. EPAC1 is essential for cardiomyocyte survival via the cAMP/Rap1 activation independently of PKA.

A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis

BACKGROUND To address the impact of antidiabetic drugs on cardiovascular safety is a matter of clinical concern. Preclinical studies revealed that various protective effects of dipeptidyl peptidase-4 inhibitor (DPP4i) on cardiovascular disease; however, its impact of on hypertension remains controversial. METHODS AND RESULTS Teneligliptin (TEN; 10mg/kg/day/p.o.) ameliorates hypertension and cardiac remodeling by normalizing a rise of angiotensin-II (AngII) that specifically observed in spontaneously hypertensive rats (SHR). TEN had no effects on vasculature and concentrations of the DPP4-related vasoactive peptides (bradykinin, neuropeptide Y, and atrial natriuretic peptide). The primary action of TEN on BP lowering was due to restoring the AngII-induced manifestation of congestive heart failure observed in SHR. Sodium-proton pump exchanger type 1 (NHE-1) is a regulator of intracellular acidity (pHi) and implicated pathophysiological role in cardiac remodeling occurred in diseased myocardium. Cardiac NHE-1 expression level was increased in SHR and this was restored in TEN-treated SHR. AngII directly augmented cardiac NHE-1 expression and its activity that contributed to hypertrophic response. TEN attenuated the AngII-induced cardiac hypertrophy with decline in pHi via suppression of NHE-1. Loss of NHE-1 activity by specific inhibitor or RNA silencing promoted intracellular acidification and consistently attenuated the AngII-mediated cardiac hypertrophy. CONCLUSION The present study revealed the protective actions of TEN on hypertension and comorbid cardiac remodeling via AngII/NHE-1 axis and the novel pathophysiological roles of intracellular acidification via NHE-1 in cardiac hypertrophy.