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Article

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

1
Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA
2
Vascular Biology Center, Augusta University, Augusta, GA 30912, USA
3
Center for Blood Disorders, Augusta University, Augusta, GA 30912, USA
4
Rocky Mountain Regional VA Center, Aurora, CO 80045, USA
5
Division of Infectious Diseases, Department of Medicine, University of Colorado Denver, Denver, CO 80204, USA
6
Division of Critical Care Medicine, Department of Pediatrics, University of Colorado Denver, Denver, CO 80204, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Andrea Olschewski, Valentina Biasin, Chandran Nagaraj and Bence Nagy
Int. J. Mol. Sci. 2021, 22(18), 9916; https://doi.org/10.3390/ijms22189916
Received: 30 July 2021 / Revised: 1 September 2021 / Accepted: 10 September 2021 / Published: 14 September 2021
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. View Full-Text
Keywords: butyrate; pulmonary hypertension; vascular remodeling; inflammation; vascular permeability; endothelial barrier; HDAC inhibitors; protein acetylation butyrate; pulmonary hypertension; vascular remodeling; inflammation; vascular permeability; endothelial barrier; HDAC inhibitors; protein acetylation
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MDPI and ACS Style

Karoor, V.; Strassheim, D.; Sullivan, T.; Verin, A.; Umapathy, N.S.; Dempsey, E.C.; Frank, D.N.; Stenmark, K.R.; Gerasimovskaya, E. The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension. Int. J. Mol. Sci. 2021, 22, 9916. https://doi.org/10.3390/ijms22189916

AMA Style

Karoor V, Strassheim D, Sullivan T, Verin A, Umapathy NS, Dempsey EC, Frank DN, Stenmark KR, Gerasimovskaya E. The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension. International Journal of Molecular Sciences. 2021; 22(18):9916. https://doi.org/10.3390/ijms22189916

Chicago/Turabian Style

Karoor, Vijaya, Derek Strassheim, Timothy Sullivan, Alexander Verin, Nagavedi S. Umapathy, Edward C. Dempsey, Daniel N. Frank, Kurt R. Stenmark, and Evgenia Gerasimovskaya. 2021. "The Short-Chain Fatty Acid Butyrate Attenuates Pulmonary Vascular Remodeling and Inflammation in Hypoxia-Induced Pulmonary Hypertension" International Journal of Molecular Sciences 22, no. 18: 9916. https://doi.org/10.3390/ijms22189916

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