Skip to main content
Top
Published in: BMC Cardiovascular Disorders 1/2021

Open Access 01-12-2021 | Pulmonary Hypertension | Research

High-fat diet attenuates the improvement of hypoxia-induced pulmonary hypertension in mice during reoxygenation

Authors: Koichi Sugimoto, Tetsuro Yokokawa, Tomofumi Misaka, Takashi Kaneshiro, Akiomi Yoshihisa, Kazuhiko Nakazato, Yasuchika Takeishi

Published in: BMC Cardiovascular Disorders | Issue 1/2021

Login to get access

Abstract

Background

It is widely recognized that metabolic disorder is associated with pulmonary hypertension (PH). It is known that hypoxia-induced elevated pulmonary artery pressure in mice returns to normal pressure during reoxygenation. However, it is still unclear how metabolic disorder affects the reverse remodeling of pulmonary arteries. In this study, we investigated the effects of high-fat diet (HFD) on the decrease in pulmonary artery pressure and reverse remodeling of pulmonary arteries in mice with hypoxia-induced PH.

Methods

We used female C57BL/6 mice aged 8 weeks. After being exposed to hypoxia (10% oxygen for four weeks) to induce PH, the mice were returned to normoxic conditions and randomized into a normal diet (ND) group and HFD group. Both groups were fed with their respective diets for 12 weeks.

Results

The Fulton index and right ventricular systolic pressure measured by a micro-manometer catheter were significantly higher in the HFD group than in the ND group at 12 weeks after reoxygenation. The medial smooth muscle area was larger in the HFD group. Caspase-3 activity in the lung tissue of the HFD group was decreased, and the apoptosis of pulmonary smooth muscle cells was suppressed after reoxygenation. Moreover, the expression levels of peroxisome proliferator-activated receptor-γ and apelin were lower in the HFD group than in the ND group.

Conclusions

The results suggest that metabolic disorder may suppress pulmonary artery reverse remodeling in mice with hypoxia-induced PH during reoxygenation.
Appendix
Available only for authorised users
Literature
2.
go back to reference Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest. 2000;106(6):733–8.CrossRef Voelkel NF, Tuder RM. Hypoxia-induced pulmonary vascular remodeling: a model for what human disease? J Clin Invest. 2000;106(6):733–8.CrossRef
3.
go back to reference Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297–309.CrossRef Shimoda LA, Laurie SS. Vascular remodeling in pulmonary hypertension. J Mol Med (Berl). 2013;91(3):297–309.CrossRef
4.
go back to reference Chen J, Wang YX, Dong MQ, Zhang B, Luo Y, Niu W, et al. Reoxygenation reverses hypoxic pulmonary arterial remodeling by inducing smooth muscle cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction. J Am Heart Assoc. 2017;6(6):e005602.PubMedPubMedCentral Chen J, Wang YX, Dong MQ, Zhang B, Luo Y, Niu W, et al. Reoxygenation reverses hypoxic pulmonary arterial remodeling by inducing smooth muscle cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction. J Am Heart Assoc. 2017;6(6):e005602.PubMedPubMedCentral
5.
go back to reference Sluiter I, van Heijst A, Haasdijk R, Kempen MB, Boerema-de Munck A, Reiss I, et al. Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats. Exp Mol Pathol. 2012;93(1):66–73.CrossRef Sluiter I, van Heijst A, Haasdijk R, Kempen MB, Boerema-de Munck A, Reiss I, et al. Reversal of pulmonary vascular remodeling in pulmonary hypertensive rats. Exp Mol Pathol. 2012;93(1):66–73.CrossRef
6.
go back to reference Riley DJ, Thakker-Varia S, Wilson FJ, Poiani GJ, Tozzi CA. Role of proteolysis and apoptosis in regression of pulmonary vascular remodeling. Physiol Res. 2000;49:577–85.PubMed Riley DJ, Thakker-Varia S, Wilson FJ, Poiani GJ, Tozzi CA. Role of proteolysis and apoptosis in regression of pulmonary vascular remodeling. Physiol Res. 2000;49:577–85.PubMed
7.
go back to reference Ussavarungsi K, Thomas CS, Burger CD. Prevalence of metabolic syndrome in patients with pulmonary hypertension. Clin Respir J. 2017;11(6):721–6.CrossRef Ussavarungsi K, Thomas CS, Burger CD. Prevalence of metabolic syndrome in patients with pulmonary hypertension. Clin Respir J. 2017;11(6):721–6.CrossRef
8.
go back to reference Maron BA, Leopold JA, Hemnes AR. Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension. Br J Pharmacol. 2020;177(7):1457–71.CrossRef Maron BA, Leopold JA, Hemnes AR. Metabolic syndrome, neurohumoral modulation, and pulmonary arterial hypertension. Br J Pharmacol. 2020;177(7):1457–71.CrossRef
9.
go back to reference Calvier L, Boucher P, Herz J, Hansmann G. LRP1 Deficiency in vascular SMC leads to pulmonary arterial hypertension that is reversed by PPARγ activation. Circ Res. 2019;124(12):1778–85.CrossRef Calvier L, Boucher P, Herz J, Hansmann G. LRP1 Deficiency in vascular SMC leads to pulmonary arterial hypertension that is reversed by PPARγ activation. Circ Res. 2019;124(12):1778–85.CrossRef
10.
go back to reference Yeligar SM, Kang BY, Bijli KM, Kleinhenz JM, Murphy TC, Torres G, et al. PPARγ regulates mitochondrial structure and function and human pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol. 2018;58(5):648–57.CrossRef Yeligar SM, Kang BY, Bijli KM, Kleinhenz JM, Murphy TC, Torres G, et al. PPARγ regulates mitochondrial structure and function and human pulmonary artery smooth muscle cell proliferation. Am J Respir Cell Mol Biol. 2018;58(5):648–57.CrossRef
11.
go back to reference Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, et al. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest. 2011;121(9):3735–46.CrossRef Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, et al. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest. 2011;121(9):3735–46.CrossRef
12.
go back to reference Keleher MR, Zaidi R, Shah S, Oakley ME, Pavlatos C, El Idrissi S, Xing X, Li D, Wang T, Cheverud JM. Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS ONE. 2018;13(2):e0192606.CrossRef Keleher MR, Zaidi R, Shah S, Oakley ME, Pavlatos C, El Idrissi S, Xing X, Li D, Wang T, Cheverud JM. Maternal high-fat diet associated with altered gene expression, DNA methylation, and obesity risk in mouse offspring. PLoS ONE. 2018;13(2):e0192606.CrossRef
13.
go back to reference Novelli EM, Little-Ihrig L, Knupp HE, Rogers NM, Yao M, Baust JJ, Meijles D, St Croix CM, Ross MA, Pagano PJ, DeVallance ER, Miles G, Potoka KP, Isenberg JS, Gladwin MT. Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2019;316(6):L1150–64.CrossRef Novelli EM, Little-Ihrig L, Knupp HE, Rogers NM, Yao M, Baust JJ, Meijles D, St Croix CM, Ross MA, Pagano PJ, DeVallance ER, Miles G, Potoka KP, Isenberg JS, Gladwin MT. Vascular TSP1-CD47 signaling promotes sickle cell-associated arterial vasculopathy and pulmonary hypertension in mice. Am J Physiol Lung Cell Mol Physiol. 2019;316(6):L1150–64.CrossRef
14.
go back to reference Sugimoto K, Nakazato K, Sato A, Suzuki S, Yoshihisa A, Machida T, et al. Autoimmune disease mouse model exhibits pulmonary arterial hypertension. PLoS ONE. 2017;12(9):e0184990.CrossRef Sugimoto K, Nakazato K, Sato A, Suzuki S, Yoshihisa A, Machida T, et al. Autoimmune disease mouse model exhibits pulmonary arterial hypertension. PLoS ONE. 2017;12(9):e0184990.CrossRef
15.
go back to reference Nakanishi N, Ogata T, Naito D, Miyagawa K, Taniguchi T, Hamaoka T, et al. MURC deficiency in smooth muscle attenuates pulmonary hypertension. Nat Commun. 2016;7:12417.CrossRef Nakanishi N, Ogata T, Naito D, Miyagawa K, Taniguchi T, Hamaoka T, et al. MURC deficiency in smooth muscle attenuates pulmonary hypertension. Nat Commun. 2016;7:12417.CrossRef
16.
go back to reference Misaka T, Murakawa T, Nishida K, Omori Y, Taneike M, Omiya S, et al. FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice. J Mol Cell Cardiol. 2018;114:93–104.CrossRef Misaka T, Murakawa T, Nishida K, Omori Y, Taneike M, Omiya S, et al. FKBP8 protects the heart from hemodynamic stress by preventing the accumulation of misfolded proteins and endoplasmic reticulum-associated apoptosis in mice. J Mol Cell Cardiol. 2018;114:93–104.CrossRef
17.
go back to reference Sakamoto T, Ishibashi T, Sakamoto N, Sugimoto K, Egashira K, Ohkawara H, et al. Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion. Arterioscler Thromb Vasc Biol. 2005;25(9):2005–11.CrossRef Sakamoto T, Ishibashi T, Sakamoto N, Sugimoto K, Egashira K, Ohkawara H, et al. Endogenous NO blockade enhances tissue factor expression via increased Ca2+ influx through MCP-1 in endothelial cells by monocyte adhesion. Arterioscler Thromb Vasc Biol. 2005;25(9):2005–11.CrossRef
18.
go back to reference Sugimoto K, Ishibashi T, Sawamura T, Inoue N, Kamioka M, Uekita H, et al. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc Res. 2009;84(1):127–36.CrossRef Sugimoto K, Ishibashi T, Sawamura T, Inoue N, Kamioka M, Uekita H, et al. LOX-1-MT1-MMP axis is crucial for RhoA and Rac1 activation induced by oxidized low-density lipoprotein in endothelial cells. Cardiovasc Res. 2009;84(1):127–36.CrossRef
19.
go back to reference Irwin DC, Garat CV, Crossno JT Jr, MacLean PS, Sullivan TM, Erickson PF, et al. Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia. Pulm Circ. 2014;4(4):638–53.CrossRef Irwin DC, Garat CV, Crossno JT Jr, MacLean PS, Sullivan TM, Erickson PF, et al. Obesity-related pulmonary arterial hypertension in rats correlates with increased circulating inflammatory cytokines and lipids and with oxidant damage in the arterial wall but not with hypoxia. Pulm Circ. 2014;4(4):638–53.CrossRef
20.
go back to reference Renshall L, Arnold N, West L, Braithwaite A, Pickworth J, Walker R, et al. Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E-/- model of PAH and atherosclerosis. Pulm Circ. 2018;8(1):2045893217752328.CrossRef Renshall L, Arnold N, West L, Braithwaite A, Pickworth J, Walker R, et al. Selective improvement of pulmonary arterial hypertension with a dual ETA/ETB receptors antagonist in the apolipoprotein E-/- model of PAH and atherosclerosis. Pulm Circ. 2018;8(1):2045893217752328.CrossRef
21.
go back to reference Pan M, Han Y, Si R, Guo R, Desai A, Makino A. Hypoxia-induced pulmonary hypertension in type 2 diabetic mice. Pulm Circ. 2017;7(1):175–85.CrossRef Pan M, Han Y, Si R, Guo R, Desai A, Makino A. Hypoxia-induced pulmonary hypertension in type 2 diabetic mice. Pulm Circ. 2017;7(1):175–85.CrossRef
22.
go back to reference Umar S, Ruffenach G, Moazeni S, Vaillancourt M, Hong J, Cunningham C, et al. Involvement of low-density lipoprotein receptor in the pathogenesis of pulmonary hypertension. J Am Heart Assoc. 2020;9(2):e012063.CrossRef Umar S, Ruffenach G, Moazeni S, Vaillancourt M, Hong J, Cunningham C, et al. Involvement of low-density lipoprotein receptor in the pathogenesis of pulmonary hypertension. J Am Heart Assoc. 2020;9(2):e012063.CrossRef
23.
go back to reference Hsieh CC, Yen MH, Yen CH, Lau YT. Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovasc Res. 2001;49(1):135–45.CrossRef Hsieh CC, Yen MH, Yen CH, Lau YT. Oxidized low density lipoprotein induces apoptosis via generation of reactive oxygen species in vascular smooth muscle cells. Cardiovasc Res. 2001;49(1):135–45.CrossRef
24.
go back to reference Kattoor AJ, Kanuri SH, Mehta JL. Role of Ox-LDL and LOX-1 in atherogenesis. Curr Med Chem. 2019;26(9):1693–700.CrossRef Kattoor AJ, Kanuri SH, Mehta JL. Role of Ox-LDL and LOX-1 in atherogenesis. Curr Med Chem. 2019;26(9):1693–700.CrossRef
25.
go back to reference Locher R, Brandes RP, Vetter W, Barton M. Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases. Hypertension. 2002;39(2 Pt 2):645–50.CrossRef Locher R, Brandes RP, Vetter W, Barton M. Native LDL induces proliferation of human vascular smooth muscle cells via redox-mediated activation of ERK 1/2 mitogen-activated protein kinases. Hypertension. 2002;39(2 Pt 2):645–50.CrossRef
26.
go back to reference Damián-Zamacona S, Toledo-Ibelles P, Ibarra-Abundis MZ, Uribe-Figueroa L, Hernández-Lemus E, Macedo-Alcibia KP, et al. Early transcriptomic response to LDL and oxLDL in human vascular smooth muscle cells. PLoS ONE. 2016;11(10):e0163924.CrossRef Damián-Zamacona S, Toledo-Ibelles P, Ibarra-Abundis MZ, Uribe-Figueroa L, Hernández-Lemus E, Macedo-Alcibia KP, et al. Early transcriptomic response to LDL and oxLDL in human vascular smooth muscle cells. PLoS ONE. 2016;11(10):e0163924.CrossRef
27.
go back to reference Heresi GA, Aytekin M, Newman J, DiDonato J, Dweik RA. Plasma levels of high-density lipoprotein cholesterol and outcomes in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(5):661–8.CrossRef Heresi GA, Aytekin M, Newman J, DiDonato J, Dweik RA. Plasma levels of high-density lipoprotein cholesterol and outcomes in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2010;182(5):661–8.CrossRef
28.
go back to reference Jonas K, Kopeć G. HDL cholesterol as a marker of disease severity and prognosis in patients with pulmonary arterial hypertension. Int J Mol Sci. 2019;20(14):3514.CrossRef Jonas K, Kopeć G. HDL cholesterol as a marker of disease severity and prognosis in patients with pulmonary arterial hypertension. Int J Mol Sci. 2019;20(14):3514.CrossRef
29.
go back to reference Cracowski JL, Labarère J, Renversez JC, Degano B, Chabot F, Humbert M. Plasma levels of high-density lipoprotein cholesterol are not associated with survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(1):107 author reply 107-8.CrossRef Cracowski JL, Labarère J, Renversez JC, Degano B, Chabot F, Humbert M. Plasma levels of high-density lipoprotein cholesterol are not associated with survival in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2012;186(1):107 author reply 107-8.CrossRef
30.
go back to reference Andersen CU, Hilberg O, Mellemkjær S, Nielsen-Kudsk JE, Simonsen U. Apelin and pulmonary hypertension. Pulm Circ. 2011;1(3):334–46.CrossRef Andersen CU, Hilberg O, Mellemkjær S, Nielsen-Kudsk JE, Simonsen U. Apelin and pulmonary hypertension. Pulm Circ. 2011;1(3):334–46.CrossRef
31.
go back to reference Brash L, Barnes GD, Brewis MJ, Church AC, Gibbs SJ, Howard LSGE, et al. Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension. JACC Basic Transl Sci. 2018;3(2):176–86.CrossRef Brash L, Barnes GD, Brewis MJ, Church AC, Gibbs SJ, Howard LSGE, et al. Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension. JACC Basic Transl Sci. 2018;3(2):176–86.CrossRef
32.
go back to reference Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, de Jesus Perez V, et al. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011;31(4):814–20.CrossRef Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, de Jesus Perez V, et al. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011;31(4):814–20.CrossRef
33.
go back to reference Archer SL, Johnson GJ, Gebhard RL, Castleman WL, Levine AS, Westcott JY, et al. Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension. J Appl Physiol (1985). 1989;66(4):1662–73.CrossRef Archer SL, Johnson GJ, Gebhard RL, Castleman WL, Levine AS, Westcott JY, et al. Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension. J Appl Physiol (1985). 1989;66(4):1662–73.CrossRef
34.
go back to reference Ciomartan TC. The n-3 polyunsaturated fatty acids: another option in the management of persistent pulmonary hypertension of the newborn? Crit Care Med. 2011;39(6):1587–9.CrossRef Ciomartan TC. The n-3 polyunsaturated fatty acids: another option in the management of persistent pulmonary hypertension of the newborn? Crit Care Med. 2011;39(6):1587–9.CrossRef
35.
go back to reference Rysz-Górzynska M, Gluba-Brzózka A, Sahebkar A, Serban MC, Mikhailidis DP, Ursoniu S, et al. Efficacy of statin therapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Sci Rep. 2016;6:30060.CrossRef Rysz-Górzynska M, Gluba-Brzózka A, Sahebkar A, Serban MC, Mikhailidis DP, Ursoniu S, et al. Efficacy of statin therapy in pulmonary arterial hypertension: a systematic review and meta-analysis. Sci Rep. 2016;6:30060.CrossRef
36.
go back to reference Anand V, Garg S, Duval S, Thenappan T. A systematic review and meta-analysis of trials using statins in pulmonary arterial hypertension. Pulm Circ. 2016;6(3):295–301.CrossRef Anand V, Garg S, Duval S, Thenappan T. A systematic review and meta-analysis of trials using statins in pulmonary arterial hypertension. Pulm Circ. 2016;6(3):295–301.CrossRef
37.
go back to reference Chen F, Yang M, Wan C, Liu L, Chen L. Efficacy and safety of statin therapy in pulmonary hypertension: a systematic review and meta-analysis. Ann Transl Med. 2019;7(23):786.CrossRef Chen F, Yang M, Wan C, Liu L, Chen L. Efficacy and safety of statin therapy in pulmonary hypertension: a systematic review and meta-analysis. Ann Transl Med. 2019;7(23):786.CrossRef
38.
go back to reference Ogawa A, Ejiri K, Matsubara H. Long-term patient survival with idiopathic/heritable pulmonary arterial hypertension treated at a single center in Japan. Life Sci. 2014;118(2):414–9.CrossRef Ogawa A, Ejiri K, Matsubara H. Long-term patient survival with idiopathic/heritable pulmonary arterial hypertension treated at a single center in Japan. Life Sci. 2014;118(2):414–9.CrossRef
Metadata
Title
High-fat diet attenuates the improvement of hypoxia-induced pulmonary hypertension in mice during reoxygenation
Authors
Koichi Sugimoto
Tetsuro Yokokawa
Tomofumi Misaka
Takashi Kaneshiro
Akiomi Yoshihisa
Kazuhiko Nakazato
Yasuchika Takeishi
Publication date
01-12-2021
Publisher
BioMed Central
Published in
BMC Cardiovascular Disorders / Issue 1/2021
Electronic ISSN: 1471-2261
DOI
https://doi.org/10.1186/s12872-021-02143-x

Other articles of this Issue 1/2021

BMC Cardiovascular Disorders 1/2021 Go to the issue