Abstract 16402: Pitx2c-Conditional Knockout Mice May Become a Useful Model to Elucidate the Pathogenesis of Post-Capillary Pulmonary Hypertension

Abstract

Introduction: Pulmonary hypertension (PH) is an intractable disease that causes cardiopulmonary dysfunction due to elevated pulmonary arterial pressure. The pathogenesis of PH varies greatly depending on whether the primary lesion is upstream or downstream of the pulmonary capillaries, and the latter, post-capillary PH (pc-PH) caused by pulmonary vein stenosis/obstruction or left heart disease, currently has not an appropriate animal models to study its pathophysiology and pharmacological effects. Hypothesis: We hypothesized that a tissue-specific deletion of a gene involved in the formation of pulmonary veins could create a pathological mouse model of pc-PH. Methods: Focusing on the homeobox transcription factor Pitx2c, which has been reported to be indispensable for the formation of pulmonary veins, we generated Pitx2c-conditional knockout (cKO) mice specific for pulmonary vein and atrial myocardium by crossing Pitx2c-floxed mouse lines with Cre mouse lines for sarcolipin, a sarcoplasmic reticulum membrane protein. Then, we examined the cardiac morphology and hemodynamics of the Pitx2c-cKO mice. Results: Tissue weights of 8-week-old Pitx2c-cKO mice showed that the relative weights of both atria (especially the right atrium), right ventricle and lungs were significantly increased in Pitx2c-cKO mice, while the relative weight of the left ventricle was decreased. Furthermore, echocardiography performed on 3-month-old Pitx2c-cKO mice revealed that the right ventricle was markedly enlarged in Pitx2c-cKO mice, with enlarged pulmonary artery annulus diameter and increased velocity time integral (VTI) of blood flow through the right ventricular outflow tract. Pitx2c-cKO mice also had significantly decreased left ventricular end-diastolic diameter (LVDd), end-systolic diameter (LVDs), and mass (LVM). On the other hand, there was no difference in left ventricular fractional shortening (%FS) or tricuspid annular plane systolic excursion (TAPSE), indicating no cardiac dysfunction in Pitx2c-cKO mice. Cardiac catheterization also revealed elevated right ventricular pressure in some Pitx2c-cKO mice. Conclusion: These primary findings suggest that the Pitx2c-cKO mice may be a model for understanding the pathogenesis of pc-PH.