The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension

Int J Mol Sci. 2021 Sep 14;22(18):9916. doi: 10.3390/ijms22189916.

Abstract

Pulmonary hypertension (PH) is a progressive cardiovascular disorder in which local vascular inflammation leads to increased pulmonary vascular remodeling and ultimately to right heart failure. The HDAC inhibitor butyrate, a product of microbial fermentation, is protective in inflammatory intestinal diseases, but little is known regarding its effect on extraintestinal diseases, such as PH. In this study, we tested the hypothesis that butyrate is protective in a Sprague-Dawley (SD) rat model of hypoxic PH. Treatment with butyrate (220 mg/kg intake) prevented hypoxia-induced right ventricular hypertrophy (RVH), hypoxia-induced increases in right ventricular systolic pressure (RVSP), pulmonary vascular remodeling, and permeability. A reversal effect of butyrate (2200 mg/kg intake) was observed on elevated RVH. Butyrate treatment also increased the acetylation of histone H3, 25-34 kDa, and 34-50 kDa proteins in the total lung lysates of butyrate-treated animals. In addition, butyrate decreased hypoxia-induced accumulation of alveolar (mostly CD68+) and interstitial (CD68+ and CD163+) lung macrophages. Analysis of cytokine profiles in lung tissue lysates showed a hypoxia-induced upregulation of TIMP-1, CINC-1, and Fractalkine and downregulation of soluble ICAM (sICAM). The expression of Fractalkine and VEGFα, but not CINC-1, TIMP-1, and sICAM was downregulated by butyrate. In rat microvascular endothelial cells (RMVEC), butyrate (1 mM, 2 and 24 h) exhibited a protective effect against TNFα- and LPS-induced barrier disruption. Butyrate (1 mM, 24 h) also upregulated tight junctional proteins (occludin, cingulin, claudin-1) and increased the acetylation of histone H3 but not α-tubulin. These findings provide evidence of the protective effect of butyrate on hypoxic PH and suggest its potential use as a complementary treatment for PH and other cardiovascular diseases.

Keywords: HDAC inhibitors; butyrate; endothelial barrier; inflammation; protein acetylation; pulmonary hypertension; vascular permeability; vascular remodeling.

MeSH terms

  • Acetylation / drug effects
  • Animals
  • Blood Pressure / drug effects
  • Butyrates / pharmacology*
  • Cytokines / metabolism
  • Endothelial Cells / drug effects
  • Heart Ventricles / drug effects
  • Heart Ventricles / physiopathology
  • Hypertension, Pulmonary / etiology*
  • Hypertension, Pulmonary / physiopathology*
  • Hypertrophy, Right Ventricular / complications
  • Hypertrophy, Right Ventricular / physiopathology
  • Hypoxia / complications*
  • Lung / blood supply
  • Lung / drug effects
  • Lung / physiopathology*
  • Macrophages / drug effects
  • Macrophages / pathology
  • Microvessels / pathology
  • Pneumonia / complications
  • Pneumonia / physiopathology*
  • Rats, Sprague-Dawley
  • Systole / drug effects
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Up-Regulation / drug effects
  • Vascular Remodeling / drug effects*

Substances

  • Butyrates
  • Cytokines