Statin-Mediated Modulation of RhoA/ROCK Signaling in Experimental Chronic Neonatal Pulmonary Hypertension
Chronic pulmonary arterial hypertension (PAH) is a debilitating and lethal disease in newborns. It is characterized by high pulmonary vascular resistance (PVR) in the lungs causing low oxygen levels and heart failure. Despite available treatments, progression of PAH is currently inevitable, leading to an early death (One-year 60% mortality rate).
Rho-kinase (ROCK) is critical to the progression of chronic PAH. Our laboratory’s work has demonstrated that ROCK inhibitors can prevent and reverse experimental PAH, at the cost of stunted growth and systemic hypotension. Statins have a clinically proven safety profile and published evidence for cholesterol-independent ROCK inhibition.
Results to-date for chronic hypoxia-exposed (CH) newborn rats shows a trend for greater elevation of PVR in females, and a greater reduction in PVR with simvastatin treatment than males. Medial wall area (MWA) and degree of muscularization are markers of pulmonary arterial remodeling in PAH. Arterial MWA in CH females is significantly increased (P<0.05) and appear to have more muscularized arteries compared to males. All pups treated with simvastatin significantly attenuated (P<0.001) both markers of remodeling, with females trending towards a greater improvement. Rescue protocol treatment had similar results with reversing pulmonary arterial remodeling (P<0.01) and trending towards significance in sex differences.