Mohammad Shafiq, Zahid Rasool Lone, Adam Olaitan Abdulkareem, Gurpreet Kaur, Sai Navya, Himalaya Singh, Kumaravelu Jagavelu, Kashif Hanif
CSIR-Central Drug Research Institute and Academy of Scientific and Innovative Research. Ann & Robert H. Lurie Children’s Hospital. University of Illorin.
India and United States
Pulmonary Pharmacology and Therapeutics
Pulm Pharmacol Ther 2023; 80:
DOI: 10.1016/j.pupt.2023.102200
Abstract
Endothelial dysfunction is critical in the pulmonary vasculature during pulmonary hypertension (PH). Moreover, in PH, increased inflammation and oxidative/nitrosative stress cause DNA damage, activating poly (ADP-ribose) polymerase-1 (PARP-1). Meloche et al. (2014) and our previous research have shown that inhibiting PARP-1 is protective in PH and associated RV hypertrophy. However, the role of PARP-1 in pulmonary arterial endothelial dysfunction has not been explored completely. Therefore, the current study aims to investigate the involvement of PARP-1 in endothelial dysfunction associated with PH. Hypoxia (1% O2) was used to induce a PH-like phenotype in human pulmonary artery endothelial cells (HPAECs), and PARP-1 inhibition was achieved via siRNA (60 nM). For the in vivo study, male Sprague Dawley rats were administered monocrotaline (MCT; 60 mg/kg, SC, once) to induce PH, and 1, 5-isoquinolinediol (ISO; 3 mg/kg) was administered daily intraperitoneally to inhibit PARP-1. PARP-1 inhibition decreased proliferation and inflammation, as well as improved mitochondrial dysfunction in hypoxic HPAECs. Furthermore, PARP-1 inhibition also promoted apoptosis by increasing DNA damage in hypoxic HPAECs. In addition, inhibition of PARP-1 reduced cell migration, VEGF expression, and tubule formation in hypoxic HPAECs. In in vivo studies, PARP-1 inhibition by ISO significantly decreased the RVP and RVH as well as improved endothelial function by increasing the pulmonary vascular reactivity and expression of p-eNOS in MCT-treated rats.
Category
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
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