Inhibition of poly (ADP-ribose) Polymerase-1 (PARP-1) improves endothelial function in pulmonary hypertension
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Date
2023
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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.