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

Vijaya Karoor,Nagavedi S Umapathy,Evgenia Gerasimovskaya,Kurt R Stenmark,Timothy Sullivan,Edward C Dempsey,Daniel N Frank,Alexander Verin,Derek Strassheim

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.

Highlights

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance and structural vascular remodeling, leading to right heart failure [1,2]
Sci. 2021, 22, 9916 we examined the beneficial effect of butyrate on multiple pathological outcomes of PH, including right ventricular systolic pressure (RVSP), right ventricular (RV) hypertrophy, pulmonary vascular remodeling, permeability, cytokine production, protein acetylation, and macrophage accumulation in the lung
SD rats exposed to hypobaric hypoxia (4 weeks; 18,000 feet elevation) demonstrated a significant increase in right ventricular systolic pressure (RVSP) and right ventricular (RV) hypertrophy (Figure 1A,B)

Summary

Introduction

Pulmonary hypertension (PH) is a progressive disease characterized by increased pulmonary vascular resistance and structural vascular remodeling, leading to right heart failure [1,2]. Different treatment strategies have been used for PH, including endothelin-1 (ET1) receptor antagonists, prostacyclin analogs, cGMPphosphodiesterase (PDE) inhibitors, and Ca2+ channel blockers, as well as some antiinflammatory and metabolic agents, which variably provide relief of symptoms [9,10,11]. These strategies do not cure the disease, indicating that the molecular mechanisms involved in the pathogenesis of PH are not completely understood

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Results

Conclusion