Abstract 19353: Prohibitin: A Potential Circulating Mitokine That May be Involved in Pulmonary Arterial Hypertension

Introduction: In Pulmonary Arterial Hypertension (PAH), a “cancer-like” mitochondrial suppression in pulmonary vascular cells underlies in part the apoptosis resistance that characterizes the proliferative vascular remodeling. There is emerging evidence that a similar mitochondrial suppression is present in extra-pulmonary tissues like the skeletal muscle or circulating cells in PAH. We speculated that this may be due to a circulating factor. In cancer, such factors may underlie muscle wasting (cancer cachexia). In worms, there is evidence that “mitokines” secreted by one organ can “condition” other organs remotely by suppressing mitochondria. We hypothesized that Prohibitin (PHB-1; a protein increased both in the tumor and in the serum of cancer patients) maybe a candidate mitokine in PAH. Results: To determine whether the pulmonary circulation responds to endogenously produced PHB-1, we studied a rat tumor xenotransplant model with CRL-2335 breast cancer cells. Rats with tumors exhibited higher PA pressures compared to rats without tumors (mPAP=12±1mmHg vs 20±2mmHg, n=18) and this increase correlated with tumor size. Importantly, this increase in PA pressures was not due to thromboembolism and was associated with increased muscularization of resistance PAs. PHB-1 levels were increased in the PAs and serum of rats with tumors compared to controls and in the culture media of CRL2335 compared to normal cells. PASMCs exposed to Recombinant (Rec)PHB-1 displayed inhibited pyruvate dehydrogenase, increased mitochondrial membrane potential (TMRM live cell imaging 37±0.5AFU vs 53±1.2AFU), decreased mitochondrial respiration and suppressed apoptosis, mimicking the PAH phenotype. Preliminary data suggested that RecPHB-1 activates the plasma membrane receptor ErbB2, which is translocated into the mitochondria (immunoblot on isolated mitochondria and immunostaining) where it acts as a negative regulator of mitochondrial function. Conclusion: The pulmonary circulation may be responsive to endogenous circulating mitochondrial inhibitors originating from extra-pulmonary tissues. PHB-1 may be a potential mitokine in PAH.