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Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn. Hypertension 2019 10;74(4):957-966

Date

09/04/2019

Pubmed ID

31476900

Pubmed Central ID

PMC6739165

DOI

10.1161/HYPERTENSIONAHA.119.13430

Scopus ID

2-s2.0-85072134040

Abstract

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of the SOD2 gene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial H2O2 formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, ola1-/- downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.

Author List

Schultz A, Olorundami OA, Teng RJ, Jarzembowski J, Shi ZZ, Kumar SN, Pritchard K Jr, Konduri GG, Afolayan AJ

Authors

Adeleye James Afolayan MD Assistant Professor in the Pediatrics department at Medical College of Wisconsin
Jason A. Jarzembowski MD, PhD Vice Chair, Chief, Professor in the Pathology department at Medical College of Wisconsin
Girija Ganesh Konduri MD Chief, Professor in the Pediatrics department at Medical College of Wisconsin
Suresh Kumar PhD Assistant Professor in the Pathology department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin
Ru-Jeng Teng MD Associate Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphatases
Animals
Apoptosis
Down-Regulation
Female
GTP-Binding Proteins
Hemodynamics
Humans
Hydrogen Peroxide
Infant, Newborn
Lung
Male
Mitochondria
Oxidative Stress
Persistent Fetal Circulation Syndrome
Proteasome Endopeptidase Complex
Reactive Oxygen Species
Sheep
Superoxide Dismutase
Ubiquitin
X-Linked Inhibitor of Apoptosis Protein
jenkins-FCD Prod-466 5b81815b8b3d1f46bfec16512ed5f574613f59c5