Sodium Butyrate Attenuates Angiotensin II‐Induced Cardiac Hypertrophy by Inhibiting COX2/PGE2 Pathway via a HDAC5/HDAC6‐Dependent Mechanism

Abstract

Sodium butyrate (NaBu) is reported to play important roles in a number of chronic diseases. The present work is aimed to investigate the effect of NaBu on angiotensin II (Ang II)‐induced cardiac hypertrophy and the underlying mechanism in in vivo and in vitro models. Male SD rats were infused with vehicle or Ang II (200 ng/d) and oral administrated with or without NaBu (1g/kg/d) for two weeks and blood pressure was monitored by the telemetry system. After two weeks, cardiac hypertrophy parameters and COX2/PGE2 pathway were analyzed by Real‐time PCR, immunohistochemistry and Western blot. The content of ANP, PGE2 and activity of HDACs were measured by ELISA. The cardiomyocyte H9C2 cells were used to investigate the underlying mechanism by which NaBu inhibiting Ang II‐mediated hypertrophy. NaBu significantly attenuated Ang II‐induced increase in the mean arterial pressure from 159 ±8 mmHg to 127 ± 7 mmHg (P<0.01). Ang II treatment remarkably increased cardiac hypertrophy as indicated by increased ration of heart weight/body weight and enlarged cardiomyocyte size, extensive fibrosis and inflammation, as well as enhanced expresssion of hypertrophic markers, whereas hearts from NaBu treated rats exhibited a significant reduction in these hypertrophic responses. Mechanistically, NaBu suppressed the expression of COX2/PGE2 along with the production of ANP and phosphorylated ERK (pERK) stimulated by Ang II in vivo and in vitro, which is mediated by the inhibition of HDAC5 and HDAC6 activities. Additionally, expression knockdown of HDAC5 and HDAC6 via gene editing strategy dramatically blocked the hypertrophic response of COX2/PGE2 pathway induced by Ang II in vitro. These results provide solid evidence that NaBu attenuates Ang II‐induced cardiac hypertrophy by inhibiting the activation of COX2/PGE2 pathway in a HDAC5/HDAC6‐dependent manner.Support or Funding InformationNational Natural Science Foundation of China (No. 81600322, No. 81770707, No. 81603587)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.