循環器ジャーナル71巻4号

2023年10月発行

特集 変革期を迎えた肺高血圧症—次世代の病態理解，診断，治療とは？ Ⅲ.肺高血圧症における最新トピックス

動物モデルを用いた肺高血圧症の病態解明と新規治療法開発

著者： 藤原隆行¹²

所属機関： ¹東京大学医学部附属病院コンピュータ画像診断学/予防医学講座 ²東京大学医学部附属病院循環器内科

ページ範囲：P.608 - P.616

POINT
●肺動脈性肺高血圧症モデル動物は複数存在し，重症度の面でモデル間での差異が大きい．
●動物モデルを用いて新規治療法開発が進められており，一部は実用に近づいている．
●病態解明のため生理的な動物モデルの確立や，新規の解析手法の応用が求められている．

参考文献

1）Gomez-Arroyo JG, Farkas L, Alhussaini AA, et al. The monocrotaline model of pulmonary hypertension in perspective. Am J Physiol Lung Cell Mol Physiol 2012 ; 302 : L363-9.

2）Tuder RM, Chacon M, Alger L, et al. Expression of angiogenesis-related molecules in plexiform lesions in severe pulmonary hypertension : Evidence for a process of disordered angiogenesis. J Pathol 2001 ; 195 : 367-74.

3）Taraseviciene-Stewart L, Kasahara Y, Alger L, et al. Inhibition of the vegf receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J 2001 ; 15 : 427-38.

4）Abe K, Toba M, Alzoubi A, et al. Formation of plexiform lesions in experimental severe pulmonary arterial hypertension. Circulation 2010 ; 121 : 2747-54.

5）Ciuclan L, Bonneau O, Hussey M, et al. A novel murine model of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2011 ; 184 : 1171-82.

6）Long L, Ormiston ML, Yang X, et al. Selective enhancement of endothelial bmpr-ii with bmp9 reverses pulmonary arterial hypertension. Nat Med 2015 ; 21 : 777-85.

7）Jerkic M, Kabir MG, Davies A, et al. Pulmonary hypertension in adult alk1 heterozygous mice due to oxidative stress. Cardiovasc Res 2011 ; 92 : 375-84.

8）Toporsian M, Jerkic M, Zhou YQ, et al. Spontaneous adult-onset pulmonary arterial hypertension attributable to increased endothelial oxidative stress in a murine model of hereditary hemorrhagic telangiectasia. Arterioscler Thromb Vasc Biol 2010 ; 30 : 509-17.

9）Steiner MK, Syrkina OL, Kolliputi N, et al. Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 2009 ; 104 : 236-44, 28p following 244.

10）Fujita M, Shannon JM, Irvin CG, et al. Overexpression of tumor necrosis factor-alpha produces an increase in lung volumes and pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 2001 ; 280 : L39-49.

11）Greenway S, van Suylen RJ, Du Marchie Sarvaas G, et al. S100a4/mts1 produces murine pulmonary artery changes resembling plexogenic arteriopathy and is increased in human plexogenic arteriopathy. Am J Pathol 2004 ; 164 : 253-62.

12）Evans JD, Girerd B, Montani D, et al. Bmpr2 mutations and survival in pulmonary arterial hypertension : An individual participant data meta-analysis. Lancet Respir Med 2016 ; 4 : 129-37.

13）Spiekerkoetter E, Tian X, Cai J, et al. Fk506 activates bmpr2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013 ; 123 : 3600-13.

14）Spiekerkoetter E, Sung YK, Sudheendra D, et al. Randomised placebo-controlled safety and tolerability trial of fk506（tacrolimus）for pulmonary arterial hypertension. Eur Respir J 2017 ; 50 : 1602449.

15）Yung LM, Yang P, Joshi S, et al. Actriia-fc rebalances activin/gdf versus bmp signaling in pulmonary hypertension. Sci Transl Med 2020 ; 12 : eaaz5660.

16）Hoeper MM, Badesch DB, Ghofrani HA, et al. Phase 3 trial of sotatercept for treatment of pulmonary arterial hypertension. N Engl J Med 2023 ; 388 : 1478-90.

17）Bhargava A, Kumar A, Yuan N, et al. Monocrotaline induces interleukin-6 mrna expression in rat lungs. Heart Dis 1999 ; 1 : 126-32.

18）Hashimoto-Kataoka T, Hosen N, Sonobe T, et al. Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A 2015 ; 112 : E2677-86.

19）Savale L, Tu L, Rideau D, et al. Impact of interleukin-6 on hypoxia-induced pulmonary hypertension and lung inflammation in mice. Respir Res 2009 ; 10 : 6.

20）Toshner M, Church C, Harbaum L, et al. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. Eur Respir J 2022 ; 59 : 2002463.

21）Li XQ, Wang HM, Yang CG, et al. Fluoxetine inhibited extracellular matrix of pulmonary artery and inflammation of lungs in monocrotaline-treated rats. Acta Pharmacol Sin 2011 ; 32 : 217-22.

22）Zhang LL, Lu J, Li MT, et al. Preventive and remedial application of etanercept attenuate monocrotaline-induced pulmonary arterial hypertension. Int J Rheum Dis 2016 ; 19 : 192-8.

23）Ameshima S, Golpon H, Cool CD, et al. Peroxisome proliferator-activated receptor gamma（ppargamma）expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003 ; 92 : 1162-9.

24）Calvier L, Chouvarine P, Legchenko E, et al. Ppargamma links bmp2 and tgfbeta1 pathways in vascular smooth muscle cells, regulating cell proliferation and glucose metabolism. Cell Metab 2017 ; 25 : 1118-34. e7.

25）Green DE, Murphy TC, Kang BY, et al. Ppargamma ligands attenuate hypoxia-induced proliferation in human pulmonary artery smooth muscle cells through modulation of microrna-21. PLoS One 2015 ; 10 : e0133391.

26）Nisbet RE, Bland JM, Kleinhenz DJ, et al. Rosiglitazone attenuates chronic hypoxia-induced pulmonary hypertension in a mouse model. Am J Respir Cell Mol Biol 2010 ; 42 : 482-90.

27）Legchenko E, Chouvarine P, Borchert P, et al. Ppargamma agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. Sci Transl Med 2018 ; 10 : eaao0303.

28）Omura J, Satoh K, Kikuchi N, et al. Protective roles of endothelial amp-activated protein kinase against hypoxia-induced pulmonary hypertension in mice. Circ Res 2016 ; 119 : 197-209.

29）Meloche J, Pflieger A, Vaillancourt M, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 2014 ; 129 : 786-97.

30）Born E, Lipskaia L, Breau M, et al. Eliminating senescent cells can promote pulmonary hypertension development and progression. Circulation 2023 ; 147 : 650-66.

31）Pankey EA, Thammasiboon S, Lasker GF, et al. Imatinib attenuates monocrotaline pulmonary hypertension and has potent vasodilator activity in pulmonary and systemic vascular beds in the rat. Am J Physiol Heart Circ Physiol 2013 ; 305 : H1288-96.

32）Ciuclan L, Hussey MJ, Burton V, et al. Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. Am J Respir Crit Care Med 2013 ; 187 : 78-89.

33）Hoeper MM, Barst RJ, Bourge RC, et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension : Results of the randomized impres study. Circulation 2013 ; 127 : 1128-38.

34）Partovian C, Adnot S, Raffestin B, et al. Adenovirus-mediated lung vascular endothelial growth factor overexpression protects against hypoxic pulmonary hypertension in rats. Am J Respir Cell Mol Biol 2000 ; 23 : 762-71.

35）Dai Z, Li M, Wharton J, et al. Prolyl-4 hydroxylase 2（phd2）deficiency in endothelial cells and hematopoietic cells induces obliterative vascular remodeling and severe pulmonary arterial hypertension in mice and humans through hypoxia-inducible factor-2alpha. Circulation 2016 ; 133 : 2447-58.

36）Voelkel NF, Gomez-Arroyo J. The role of vascular endothelial growth factor in pulmonary arterial hypertension. The angiogenesis paradox. Am J Respir Cell Mol Biol 2014 ; 51 : 474-84.

37）Masaki T, Okazawa M, Asano R, et al. Aryl hydrocarbon receptor is essential for the pathogenesis of pulmonary arterial hypertension. Proc Natl Acad Sci U S A 2021 ; 118 : e2023899118.

38）Fujiwara T, Takeda N, Hara H, et al. Three-dimensional visualization of hypoxia-induced pulmonary vascular remodeling in mice. Circulation 2021 ; 144 : 1452-5.