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

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.

The Role of Gut and Airway Microbiota in Pulmonary Arterial Hypertension

“…Liu et al found that GPR43 and GPR41 are expressed in human alveolar primary cells and regulated by intestinal-derived LPS, and directly verified the transmission of LPS and SCFA from the intestine to the lung using germ-free mice (Liu et al, 2021 ). It is reported that butyrate treatment can reverse the increase of CD68+ and CD163+ macrophages in the lungs of PAH rats induced by hypoxia (Karoor et al, 2021 ). Butyrate also exerts its anti-inflammatory effects by inhibiting the development of T helper 17 (Th17) cells and down-regulating VCAM-1 and CX3C chemokine Fractalkine in endothelial cells (Li et al, 2018 ; Chen et al, 2019 ; Karoor et al, 2021 ).…”

“…It is reported that butyrate treatment can reverse the increase of CD68+ and CD163+ macrophages in the lungs of PAH rats induced by hypoxia (Karoor et al, 2021 ). Butyrate also exerts its anti-inflammatory effects by inhibiting the development of T helper 17 (Th17) cells and down-regulating VCAM-1 and CX3C chemokine Fractalkine in endothelial cells (Li et al, 2018 ; Chen et al, 2019 ; Karoor et al, 2021 ). In addition to immune regulation, Karoor and Kim et al found that butyrate inhibited hypoxia-induced angiogenesis by decreasing the expression of VEGF-α and HIF-1α (Kim et al, 2007 ; Karoor et al, 2021 ).…”

“…Butyrate also exerts its anti-inflammatory effects by inhibiting the development of T helper 17 (Th17) cells and down-regulating VCAM-1 and CX3C chemokine Fractalkine in endothelial cells (Li et al, 2018 ; Chen et al, 2019 ; Karoor et al, 2021 ). In addition to immune regulation, Karoor and Kim et al found that butyrate inhibited hypoxia-induced angiogenesis by decreasing the expression of VEGF-α and HIF-1α (Kim et al, 2007 ; Karoor et al, 2021 ). Furthermore, butyrate plays a significant role in maintaining the integrity of pulmonary microvascular endothelial and gastrointestinal barrier (Plöger et al, 2012 ; Karoor et al, 2021 ).…”

“…In addition to immune regulation, Karoor and Kim et al found that butyrate inhibited hypoxia-induced angiogenesis by decreasing the expression of VEGF-α and HIF-1α (Kim et al, 2007 ; Karoor et al, 2021 ). Furthermore, butyrate plays a significant role in maintaining the integrity of pulmonary microvascular endothelial and gastrointestinal barrier (Plöger et al, 2012 ; Karoor et al, 2021 ). Conversely, enrichment of the Collinsella in the intestine of PAH patients increases intestinal permeability by down-regulating tight junction proteins and promotes the production of epithelial IL-17A (Kim et al, 2018 ; Kim S. et al, 2020 ).…”

The Role and Mechanism of Gut Microbiota in Pulmonary Arterial Hypertension

“…When the gut barrier is impaired, intestinal Gram-negative bacteria release lipopolysaccharides (LPS) into the bloodstream, causing Toll-like receptor 4 (TLR4)-mediated endotoxemia [ 18 , 19 ], which induces pulmonary perivascular inflammatory responses and thus promotes the development of PAH. Furthermore, variations in gut microbial metabolites facilitate perivascular inflammation and the proliferation of pulmonary vascular smooth muscle cells, thereby initiating lung injury and pulmonary vascular remodeling, and finally leading to PAH [ 20 , 21 , 22 ] ( Figure 1 ). However, the specific interaction between gut dysbiosis and PAH has not been clearly clarified.…”