Nobiletin, a Polymethoxy Flavonoid, Protects Against Cardiac Hypertrophy Induced by Pressure-Overload via Inhibition of NAPDH Oxidases and Endoplasmic Reticulum Stress

Cell Physiol Biochem. 2017;42(4):1313-1325. doi: 10.1159/000478960. Epub 2017 Jul 13.


Background/aims: An increase in oxidative stress has been implicated in the pathophysiology of pressure-overload induced cardiac hypertrophy. Nobiletin (NOB), extracted from the fruit peel of citrus, possesses anti-oxidative property. Our study aimed to investigate the protective role of NOB in the progression of cardiac hypertrophy in vivo and in vitro.

Methods: Mice received aortic banding (AB) operation to induce cardiac hypertrophy. Experimental groups were as follows: sham+vehicle (VEH/SH), sham+NOB (NOB/SH), AB+vehicle (VEH/AB), and AB+ NOB (NOB/AB). Animals (n = 15 per group) were treated with vehicle or NOB (50 mg/kg) for 4 weeks after disease onset.

Results: NOB prevented cardiac hypertrophy induced by aortic banding (AB), as assessed by the cross-sectional area of cardiomyocytes, heart weight-to-body weight ratio, gene expression of hypertrophic markers and cardiac function. In addition, NOB supplementation blunted the increased expression of NAPDH oxidase (NOX) 2 and NOX4 and mitigated endoplasmic reticulum (ER) stress and myocyte apoptosis in cardiac hypertrophy. Furthermore, NOB treatment attenuated the neonatal rat cardiomyocyte (NRCM) hypertrophic response stimulated by phenylephrine (PE) and alleviated ER stress. However, our data showed that NOB dramatically inhibited NOX2 expression but not NOX4 in vitro. Finally, we found that knockdown of NOX2 attenuated ER stress in NRCMs stimulated by PE.

Conclusions: Inhibition of oxidative and ER stress by NOB in the myocardium may represent a potential therapy for cardiac hypertrophy. Moreover, there is a direct role of NOX2 in regulating ER stress stimulated by PE.

Keywords: Cardiac hypertrophy; Endoplasmic reticulum stress; NAPDH oxidase; Nobiletin.

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Aorta / surgery
  • Body Weight / drug effects
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control*
  • Cardiotonic Agents / pharmacology*
  • Disease Progression
  • Drug Administration Schedule
  • Endoplasmic Reticulum Stress / drug effects
  • Flavones / pharmacology*
  • Gene Expression / drug effects
  • Heart / drug effects*
  • Heart / physiopathology
  • Male
  • Membrane Glycoproteins / antagonists & inhibitors*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases / antagonists & inhibitors*
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Organ Size / drug effects
  • Oxidative Stress / drug effects
  • Phenylephrine / antagonists & inhibitors
  • Phenylephrine / pharmacology
  • Primary Cell Culture


  • Antioxidants
  • Cardiotonic Agents
  • Flavones
  • Membrane Glycoproteins
  • Phenylephrine
  • nobiletin
  • Cybb protein, mouse
  • NADPH Oxidase 2
  • NADPH Oxidase 4
  • NADPH Oxidases
  • Nox4 protein, mouse