DPP (Dipeptidyl Peptidase)-4 Inhibitor Attenuates Ang II (Angiotensin II)–Induced Cardiac Hypertrophy via GLP (Glucagon-Like Peptide)-1–Dependent Suppression of Nox (Nicotinamide Adenine Dinucleotide Phosphate Oxidase) 4-HDAC (Histone Deacetylase) 4 Pathway

Abstract

Nox4 (NADPH [Nicotinamide adenine dinucleotide phosphate] oxidase 4) is a major source of oxidative stress and is intimately involved in cardiac hypertrophy. DPP (Dipeptidyl peptidase)-4 inhibitor has been reported to regulate Nox4 expression in adipose tissues. However, its effects on Nox4 in cardiac hypertrophy are still unclear. We investigated whether DPP-4 inhibitor could ameliorate cardiac hypertrophy by regulating Nox4 and its downstream targets. Ang II (Angiotensin II; 1.44 mg/kg per day) or saline was continuously infused into C57BL/6J mice with or without teneligliptin (a DPP-4 inhibitor, 30 mg/kg per day) in the drinking water for 1 week. Teneligliptin significantly suppressed plasma DPP-4 activity without any significant changing aortic blood pressure or metabolic parameters such as blood glucose and insulin levels. It attenuated Ang II–induced increases in left ventricular wall thickness and the ratio of heart weight to body weight. It also significantly suppressed Ang II–induced increases in Nox4 mRNA, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4 (histone deacetylase 4), a downstream target of Nox4 and a crucial suppressor of cardiac hypertrophy, in the heart. Exendin-3 (150 pmol/kg per minute), a GLP-1 (glucagon-like peptide 1) receptor antagonist, abrogated these inhibitory effects of teneligliptin on Nox4, 4-hydroxy-2-nonenal, phosphorylation of HDAC4, and cardiac hypertrophy. In cultured neonatal cardiomyocytes, exendin-4 (100 nmol/L, 24 hours), a GLP-1 receptor agonist, ameliorated Ang II–induced cardiomyocyte hypertrophy and decreased in Nox4, 4-hydroxy-2-nonenal, and phosphorylation of HDAC4. Furthermore, exendin-4 prevented Ang II–induced decrease in nuclear HDAC4 in cardiomyocytes. In conclusion, GLP-1 receptor stimulation by DPP-4 inhibitor can attenuate Ang II–induced cardiac hypertrophy by suppressing of the Nox4-HDAC4 axis in cardiomyocytes.

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…GLP-1RAs can have effects on inflammation and defending ER stress via suppressing NF-κB in diabetic cardiomyocyte models [152]. GLP-1R can also suppress cardiac hypertrophy induced by Ang II through attenuating the Nox4-histone deacetylase 4 (HDAC4) axis [162]. Apart from these actions, GLP-1RAs ameliorate cardiac fibrosis induced by abdominal aortic constriction via interfering with Ang II type 1 receptor signaling [163].…”

Histone deacetylase HDAC4 participates in the pathological process of myocardial ischemia-reperfusion injury via MEKK1/JNK pathway by binding to miR-206

“…Inhibition of HDAC4 can improve cardiac function and reduce myocardial infarction in mice suffering from ischemic-induced heart failure [ 33 ]. Additionally, HDAC4 deficiency can attenuate Ang II-induced cardiac hypertrophy in cardiomyocytes [ 34 ], as well as reducing cardio fibrosis in juvenile rats with overload-induced ventricular hypertrophy [ 35 ].…”

NOX-Dependent Signaling Dysregulation in Severe COVID-19: Clues to Effective Treatments

“…Many data have shown that hypertension-associated vascular functional and structural changes are attributable to NOX-driven intravascular ROS generation. Indeed, Ang II, a well-known pro-hypertensive factor, augments blood pressure activating NOX via AT1 receptor (Okabe et al, 2020). Among NOX isoforms, NOX5 exerts a relevant role in blood pressure control.…”