Simvastatin prevents and reverses chronic pulmonary hypertension in newborn rats via pleiotropic inhibition of RhoA signaling

Abstract

Chronic neonatal pulmonary hypertension (PHT) frequently results in early death. Systemically administered Rho-kinase (ROCK) inhibitors prevent and reverse chronic PHT in neonatal rats, but at the cost of severe adverse effects, including systemic hypotension and growth restriction. Simvastatin has pleiotropic inhibitory effects on isoprenoid intermediates that may limit activity of RhoA, which signals upstream of ROCK. We therefore hypothesized that statin treatment would safely limit pulmonary vascular RhoA activity and prevent and reverse experimental chronic neonatal PHT via downstream inhibitory effects on pathological ROCK activity. Sprague-Dawley rats in normoxia (room air) or moderate normobaric hypoxia (13% O) received simvastatin (2 mg·kg·day ip) or vehicle from postnatal days 1-14 (prevention protocol) or from days 14-21 (rescue protocol). Chronic hypoxia increased RhoA and ROCK activity in lung tissue. Simvastatin reduced lung content of the isoprenoid intermediate farnesyl pyrophosphate and decreased RhoA/ROCK signaling in the hypoxia-exposed lung. Preventive or rescue treatment of chronic hypoxia-exposed animals with simvastatin decreased pulmonary vascular resistance, right ventricular hypertrophy, and pulmonary arterial remodeling. Preventive simvastatin treatment improved weight gain, did not lower systemic blood pressure, and did not cause apparent toxic effects on skeletal muscle, liver or brain. Rescue therapy with simvastatin improved exercise capacity. We conclude that simvastatin limits RhoA/ROCK activity in the chronic hypoxia-exposed lung, thus preventing or ameliorating hemodynamic and structural markers of chronic PHT and improving long-term outcome, without causing adverse effects.

Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats

“…In fact, therapeutic drugs were used just under pathological condition. It has been reported that simvastatin increase neurogenesis both under pathological and physiological condition [58,59] and has no significant toxicity on neonatal rats [25]. So, we did not design a control group with simvastatin alone in the present study.…”

“…Besides cholesterol-lowering effects, simvastatin, a HMG-CoA reductase inhibitor, is known as its neuroprotection in several brain injury models such as brain ischemia, traumatic brain injury, experimental intracerebral hemorrhage, and subarachnoid hemorrhage [19][20][21][22][23] and it has no significant toxicity effects in neonatal rats [24,25]. Its therapeutic effect might be mediated by reducing vasospasm, oxidative stress, inflammation and apoptosis, promoting angiogensis and neurogenesis, restoring endothelial function and activating phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3beta (GSK-3β) signaling pathway [23,26].…”

Sodium nitrite augments lungS-nitrosylation and reverses chronic hypoxic pulmonary hypertension in juvenile rats

“…Separate animals were exposed to chronic hypoxia with or without iNO 20 ppm. Effects of rescue treatment reflect "reversal" of chronic PHT (rather than limiting further progression) as PHT markers have previously been determined in this model to remain stable between PNDs 14 and 21 (54). Each litter was maintained at n ϭ 12 pups throughout the exposure period to control for nutritional effects.…”

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

“…Overall, these data suggest that HIF-1α might be a suitable therapeutic target. Congruently, Wong et al reported that the use of Simvastatin and different Rho kinase inhibitors, which allow the cleavage of HIF-1α, reversed PH in newborn rats [103]. Moreover, micro RNA 150 alleviated hypoxia induced PH by inhibiting HIF-1α expression [103].…”

“…Congruently, Wong et al reported that the use of Simvastatin and different Rho kinase inhibitors, which allow the cleavage of HIF-1α, reversed PH in newborn rats [103]. Moreover, micro RNA 150 alleviated hypoxia induced PH by inhibiting HIF-1α expression [103]. Drugs targeting HIF-1α expression have been used to decrease PH severity[104, 105].…”