Abstract 6166: Molecular Mechanisms of Right Ventricular Failure: A Role for Vascular Endothelial Growth Factor and Endoplasmic Reticulum Stress
Background: Patients with severe chronic pulmonary hypertension (PH) frequently die from right ventricular (RV) failure. Traditionally, RV failure has been explained by the increase in afterload and RV volume overload, yet only limited information is available regarding the cellular and molecular mechanisms of RV failure. We hypothesized that the health of the lung microvasculature is a critical determinant of RV failure. To address this hypothesis we compared pulmonary artery banding (PAB), a purely mechanical model of increased afterload with a normal lung circulation, to a model of severe angioproliferative PH (SuHx) characterized by high PA pressure and lung vascular remodeling induced by the combination of treatment with the vascular endothelial growth factor (VEGF) receptor blocker SU5416 and chronic hypoxia. Specifically, we asked the question: Is VEGF compromised in RV failure and if so, is it due to endoplasmic reticulum (ER)/oxidative stress?
Methods and Results: PAB Model: Following thoracotomy, PA was dissected free of the aorta. Rats were banded using silk thread and an 18-gauge needle. The combination of fixed banding around the PA and animal growth resulted in increased RV afterload. SuHx model: Rats were injected once with SU5416 (200mg/kg), followed by chronic hypoxia (simulated altitude of 5000m in a hypobaric chamber with an inspired partial O2 pressure of ~77 mmHg) for 3 weeks, and 2 weeks at sea level. Rat RV’s were collected for mRNA (QPCR) and protein (Western Blot) quantification. Expression of VEGF and its receptors (R1, R2) was significantly reduced in the SuHx model (35%, p<0.05)). Decreased VEGF expression was associated with significant loss of RV microvasculature (ascertained using tomato lectin/DAPI staining). Expression of anti-oxidant proteins Nrf2 and heme oxygenase-1 were decreased in SuHx RV. Pro-apoptotic ER stress proteins (CHOP, GADD34) were elevated in the SuHx model but not in the PAB model (2-fold, p<0.001). Pre-treatment with the anti-oxidant protandim significantly decreased CHOP and GADD34 (50%, p<0.05).
Conclusion: Lung microvascular health is a critical determinant of RV failure. Oxidative and ER stress mediated loss of VEGF expression and signaling result in RV dysfunction and promote RV failure.