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Pulmonary Arterial Hypertension Induces Gene Expression Changes in the Right Ventricle in Advance of Right Ventricular Failure that Are More Severe in Female Rats

Ferhaan Ahmad

JC Sembrat

Revathi Rajkumar

XN Huang


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Conference: 2012 International PHA Conference and Scientific Sessions

Release Date: 06.22.2012

Presentation Type: Abstracts

BACKGROUND: Right ventricular (RV) failure is the leading cause of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), and females represent up to 75% of patients with PAH. However, most animal models of PAH focus on male rats precluding an analysis of sex-specific changes in RV adaptation or dysfunction. We analyzed genome-wide mRNA expression patterns in the RV of both female and male rat models of severe PAH to determine whether changes occur prior to the onset of RV failure, whether these changes resemble those characteristic of left ventricular (LV) failure, and whether there are sex-specific biological differences in RV failure.

METHODS: 6 week-old female and male rats underwent left pneumonectomy or sham surgery followed by 50 mg/kg MCT 7 days later to induce severe, neointimal PAH. Rats underwent transthoracic echocardiography and continuous ambulatory invasive right heart hemodynamic monitoring. Cardiac tissue was harvested and RNA expression profiles were generated by microarrays from female (n=3) and male (n=4) rats with PAH 10 days following MCT, and from female (n=4) and male (n=4) control rats.

RESULTS: Experimental rats exhibited significantly elevated pulmonary pressures but grossly normal RV size and function prior to sacrifice. 195 genes were differentially expressed in the RV of rats with PAH relative to normal control rats. These genes were involved in calcium signaling, myocyte contraction, mitochondrial function, extracellular matrix remodeling, cell proliferation, and cell membrane and cytoskeleton structure. Expression changes in Emp3, Fn1, Hspb1, Mgp, S100a4 and Timp1 were confirmed by real-time quantitative PCR in RV. Expression of these genes was unchanged in the LV. In general, female PAH rats exhibited more extreme gene expression changes than male PAH rats.

CONCLUSIONS: We have documented gene expression changes in RV of rats with PAH prior to the appearance of significant RV enlargement. These changes resemble those occurring in LV failure but appear to be more severe in female relative to male rats.