Abstract 11935: Molecular and Cellular Mechanisms of Right Ventricular Remodeling in Pulmonary Hypertension
Background: Pulmonary hypertension (PH) causes elevated right ventricular (RV) systolic pressure, RV remodeling and finally RV failure to death. However, the roles of endothelial nitric oxide (NO) pathway and collagen metabolism caused by PH in the RV remodeling remain to be fully elucidated.
Methods and Results: First, we examined RV autopsy samples from 6 PH patients with RV failure (27 to 72 yrs.) and age/sex-matched 3 controls who died of non-cardiac causes. Next, we examined RV remodeling in 2 mouse models of chronic hypoxia-induced PH with endothelial NO synthase-deficient (eNOS-/-) (n=7~12) and collagenase-resistant knock-in (ColR/R) mice (n=7~11). In humans, RV failure was associated with RV hypertrophy, interstitial and perivascular fibrosis, decreased RV capillary density and increased macrophage recruitment, while there was no significant difference in leucocyte recruitment into the RV free wall. Furthermore, immunostaining showed that coronary matrix metalloproteinase (MMP)-2 and Rho-kinase activity (as evaluated by the extent of phosphorylation of myosin binding subunit (p-MBS), a substrate of Rho-kinase) were increased in PH patients with RV failure. In contrast, there was no difference in the expression of MMP9 or Rho-kinase isoforms (ROCK1 and ROCK2) between controls and PH patients with RV failure. In animal experiments with chronic hypoxia, eNOS-/- mice developed higher hemodynamic changes compared with WT mice, while ColR/R mice developed comparable hemodynamic changes with WT mice. Both hypoxic eNOS-/- and ColR/R mice developed greater extent of RV hypertrophy, perivascular remodeling and macrophage infiltration compared with WT mice. Capillary rarefaction was developed in hypoxic eNOS-/- mice, whereas hypoxic ColR/R mice were able to increase their capillary density in the RV. Both mouse models showed enhanced autophagy both under normoxic condition and in response to hypoxia.
Conclusions: These results indicate that RV remodeling occurs early during PH development through fibrosis, perivascular remodeling, capillary rarefaction and autophagy, for which eNOS pathway and collagen metabolism may be substantially involved.
- © 2013 by American Heart Association, Inc.