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

Hypertension. 2020 Apr;75(4):991-1001. doi: 10.1161/HYPERTENSIONAHA.119.14400. Epub 2020 Mar 11.

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.

Keywords: angiotensins; blood pressure; hypertrophy; oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II
  • Animals
  • Blood Pressure / drug effects
  • Cardiomegaly / chemically induced
  • Cardiomegaly / drug therapy*
  • Cardiomegaly / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidase IV Inhibitors / therapeutic use*
  • Glucagon-Like Peptide 1 / metabolism*
  • Heart Rate / drug effects
  • Histone Deacetylases / metabolism*
  • Mice
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • NADPH Oxidase 4 / metabolism*
  • Oxidative Stress / drug effects
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Rats
  • Signal Transduction / drug effects*
  • Thiazolidines / pharmacology
  • Thiazolidines / therapeutic use*

Substances

  • 3-(4-(4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl)pyrrolidin-2-ylcarbonyl)thiazolidine
  • Dipeptidyl-Peptidase IV Inhibitors
  • Pyrazoles
  • Thiazolidines
  • Angiotensin II
  • Glucagon-Like Peptide 1
  • NADPH Oxidase 4
  • Hdac5 protein, mouse
  • Histone Deacetylases