Molecular and physiological alterations in murine ventricular dysfunction.
The present study reports the development and characterization of a murine model of right ventricular dysfunction following graded constriction in the pulmonary artery via microsurgical approaches. To analyze in vivo ventricular function, a technique of x-ray contrast microangiography was developed to allow the quantitative analysis of ventricular volumes and of ejection fraction in normal and pressure-overloaded right ventricle. Severe, chronic pulmonary arterial banding for 14 days resulted in right ventricular dilatation and dysfunction, associated with right atrial enlargement, and angiographic evidence of tricuspid regurgitation. These effects were dependent on the extent of hemodynamic overload, since more moderate pulmonary arterial constriction resulted in hypertrophy with maintenance of right ventricular function. With severe pulmonary artery constriction, the murine right ventricle displays a failing heart phenotype including chamber dilation with reduced function that resembles right ventricular dysfunction in man during chronic pulmonary arterial hypertension. Northern and immunoblot analyses demonstrate a marked down-regulation of phospholamban mRNA and its corresponding protein with both levels of constriction, while a less pronounced but significant depression of sarcoplasmic reticulum Ca(2+)-ATPase protein was observed with severe overload, suggesting that this pattern is an early genetic marker of ventricular dysfunction. By coupling mouse genetics with this murine model and the ability to assess cardiac function in vivo, one should be able to test the role of the down-regulation of phospholamban and other defined alterations in the cardiac muscle gene program in the onset of the failing heart phenotype.
Rockman, HA; Ono, S; Ross, RS; Jones, LR; Karimi, M; Bhargava, V; Ross, J; Chien, KR
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