RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension

被引：7

作者：

Piper, Bryce ^{[1
,2
]}

Bogamuwa, Srimathi ^{[1
,2
]}

Hossain, Tanvir ^{[3
]}

Farkas, Daniela ^{[1
,2
]}

Rosas, Lorena ^{[1
,2
]}

Green, Adam C.

Newcomb, Geoffrey ^{[1
,2
]}

Sun, Nuo ^{[2
,4
]}

Ovando-Ricardez, Jose A. ^{[1
,2
]}

Horowitz, Jeffrey C. ^{[1
,2
]}

Bhagwani, Aneel R. ^{[1
,2
,5
]}

Yang, Hu ^{[6
]}

Kudryashova, Tatiana V. ^{[7
]}

Rojas, Mauricio ^{[1
,2
]}

Mora, Ana L. ^{[1
,2
]}

Yan, Pearlly ^{[8
,9
]}

Mallampalli, Rama K. ^{[1
,2
]}

Goncharova, Elena A. ^{[10
]}

Eckmann, David M. ^{[3
,11
]}

Farkas, Laszlo ^{[1
,2
,12
]}

机构：

[1] Ohio State Univ OSU, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Columbus, OH USA

[2] Ohio State Univ OSU, Davis Heart & Lung Res Inst, Columbus, OH USA

[3] Ohio State Univ OSU, Dept Anesthesiol, Columbus, OH USA

[4] Ohio State Univ OSU, Dept Cell Biol & Physiol, Columbus, OH USA

[5] Ziauddin Univ, Dept Physiol, Karachi, Pakistan

[6] Missouri Univ Sci & Technol, Linda & Bipin Doshi Dept Chem & Biochem Engn, Rolla, MO USA

[7] Univ Pittsburgh, Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA USA

[8] OSU, Dept Internal Med, Div Hematol, Columbus, OH USA

[9] OSU, James Canc Ctr, Columbus, OH USA

[10] Univ Calif Davis, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Davis, CA USA

[11] OSU, Ctr Med & Engn Innovat, Columbus, OH USA

[12] Davis Heart & Lung Res Inst, Div Pulm Crit Care & Sleep Med, Dept Internal Med, 473 W 12th Ave, Columbus, OH 43210 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2024年 / 134卷 / 03期

关键词：

TO-MESENCHYMAL TRANSITION; CELL PROLIFERATION; APOPTOSIS; INHIBITION; AUTOPHAGY; MITOPHAGY; SURVIVAL;

D O I：

10.1172/JCI169441

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML -098 reduced established PH in rats with chronic hypoxia/ SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.

引用

页码：1 / 10

页数：15