Yi-Jen Chen

Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). Chronic inflammation and derangement of myocardial energy and lipid homeostasis are common features of DM. The transcription factors of peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, which are important in regulating energy and lipid homeostasis. There are three PPAR isoforms, α, γ, and δ, and their roles have been increasingly recognized to be important in CVD. These three isoforms are expressed in the heart and play pivotal roles in myocardial lipid metabolism, as well as glucose and energy homeostasis, and contribute to extra metabolic roles with effects on inflammation and oxidative stress. Moreover, regulation of PPARs may have significant effects on cardiac electrical activity and arrhythmogenesis. This review describes the roles of PPARs and their agonists in DM cardiomyopathy, inflammation, and cardiac electrophysiology.

The dipeptidyl peptidase-4 inhibitor-sitagliptin modulates calcium dysregulation, inflammation, and PPARs in hypertensive cardiomyocytes

BACKGROUND Hypertension induces cardiac dysfunction, calcium (Ca(2+)) dysregulation, and arrhythmogenesis. Dipeptidyl peptidase (DPP)-4 inhibitors, an antidiabetic agent with anti-inflammation and anti-hypertension potential, may regulate peroxisome proliferator-activated receptors (PPARs)-α, -γ, and -δ and Ca(2+) homeostasis. OBJECTIVE The purpose of this study was to investigate whether DPP-4 inhibitor, sitagliptin, can modulate PPARs and Ca(2+) handling proteins in hypertensive hearts. METHODS A Western blot analysis was used to evaluate protein expressions of myocardial PPAR isoforms, tumor necrosis factor (TNF)-α, interleukin (IL)-6, sarcoplasmic reticulum ATPase (SERCA2a), Na(+)-Ca(2+) exchanger (NCX), ryanodine receptor (RyR), voltage-dependent Ca(2+) (CaV1.2), slow-voltage potassium currents (Kvs), angiotensin II type 1 receptor (AT1R), and receptor of advanced glycated end-products (RAGE) from Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with sitagliptin (10mg/kg for 4weeks). Conventional microelectrodes were used to record action potentials (APs) in the ventricular myocytes from each group. RESULTS Compared to the control group, SHR had lower cardiac PPAR-α and PPAR-δ protein expressions, but had greater cardiac PPAR-γ levels, and TNF-α, IL-6, RAGE, and AT1R protein expressions, which were ameliorated in the sitagliptin-treated SHR. SHR had prolonged QT interval and AP duration with less SERCA2a and RyR, and greater CaV1.2 expressions, which were also attenuated in sitagliptin-treated SHR. CONCLUSIONS Sitagliptin significantly changed the cardiac electrophysiological characteristics and Ca(2+) regulation, which may have been caused by its effects on cardiac PPARs, proinflammatory cytokines, and AT1R.

Effect of Nitric Oxide on Strophanthidin-Induced Ventricular Tachycardia

Nitric oxide (NO) has been demonstrated to have several effects on the heart. Through the stimulation of guanylate cyclase, NO increases cyclic GMP and decreases intracellular calcium. The purpose of this study was to evaluate the effects of NO on ventricular arrhythmia induced by strophanthidin in guinea pigs and dogs. In experiment 1, after strophanthidin-induced ventricular tachycardia, guinea pigs received different doses of L-arginine (0, 25, 50, 100, 200, and 400 mg/kg; n = 10 for each dose), 200 mg/kg L-arginine combined with 100 mg/kg NG-nitro-L-arginine methylester (L-NAME, n = 10), or 200 mg/kg D-arginine (n = 10). In experiment 2, after strophanthidin-induced ventricular tachycardia, dogs (n = 7) received 200 mg/kg L-arginine. By 12-lead ECG, monophasic action potentials in left and right ventricles were recorded throughout the study. In experiment 1, guinea pigs which received 200 mg/kg or 400 mg/kg L-arginine had greater incidences of ventricular tachycardia termination (60 and 80%, respectively) than those which received 0, 25, 50, and 100 mg/kg L-arginine (0, 0, 20, and 30%, respectively), those which received L-arginine with L-NAME (0%), and those which received D-arginine (0%). In experiment 2, 5 (71%) of the dogs had successful termination of ventricular tachycardia. These findings suggest that L-arginine was effective in treating strophanthidin-induced ventricular tachycardia in vivo and that the underlying mechanism is through a NO pathway.