NADPH oxidase-mediated endothelial injury in HIV- and opioid-induced pulmonary arterial hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 318; no. 5; pp. L1097 - L1108
• Main Authors: Agarwal, Stuti, Sharma, Himanshu, Chen, Ling, Dhillon, Navneet K
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2020
• Subjects: Analgesics, Opioid - pharmacology; Animals; Autophagy - drug effects; Autophagy - genetics; Cell Proliferation - drug effects; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Gene Expression Regulation; HIV-1 - genetics; HIV-1 - metabolism; Humans; Lung - drug effects; Lung - metabolism; Lung - pathology; Male; Mitochondria - drug effects; Mitochondria - metabolism; Morphine - pharmacology; NADPH Oxidase 2 - genetics; NADPH Oxidase 2 - metabolism; NADPH Oxidase 4 - genetics; NADPH Oxidase 4 - metabolism; Oxidative Stress; Pulmonary Arterial Hypertension - chemically induced; Pulmonary Arterial Hypertension - genetics; Pulmonary Arterial Hypertension - metabolism; Rats; Rats, Inbred F344; Rats, Transgenic; Reactive Oxygen Species - metabolism; tat Gene Products, Human Immunodeficiency Virus - genetics; tat Gene Products, Human Immunodeficiency Virus - metabolism; tat Gene Products, Human Immunodeficiency Virus - pharmacology; Vascular Remodeling - drug effects; Vascular Remodeling - genetics; apoptosis; autophagy; HIV-Tat; proliferation; opioids
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00480.2019

We previously demonstrated that the combined exposure of human pulmonary microvascular endothelial cells (HPMECs) to morphine and viral protein(s) results in the oxidative stress-mediated induction of autophagy, leading to shift in the cells from early apoptotic to apoptosis-resistant proliferative status associated with the angioproliferative remodeling observed in pulmonary arterial hypertension (PAH). In this study, we tried to delineate the major source of HIV-1 protein Tat and morphine induced oxidative burst in HPMECs and its consequences on vascular remodeling and PAH in an in vivo model. We observed switch from the initial increased expression of NADPH oxidase (NOX) 2 in response to acute treatment of morphine and HIV-Tat to later increased expression of NOX4 on chronic treatment in the endoplasmic reticulum of HPMECs without any alterations in the mitochondria. Furthermore, NOX-dependent induction of autophagy was observed to play a pivotal role in regulating the endothelial cell survival. Our in vivo findings showed significant increase in pulmonary vascular remodeling, right ventricular systolic pressure, and Fulton index in HIV-transgenic rats on chronic administration of morphine. This was associated with increased oxidative stress in lung tissues and rat pulmonary microvascular endothelial cells. Additionally, endothelial cells from morphine-treated HIV-transgenic rats demonstrated increased expression of NOX2 and NOX4 proteins, inhibition of which ameliorated their increased survival upon serum starvation. In conclusion, this study describes NADPH oxidases as one of the main players in the oxidative stress-mediated endothelial dysfunction on the dual hit of HIV-viral protein(s) and opioids.