Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the β-adrenergic and renin-angiotensin systems.
Aortic valve regurgitation (AR) imposes a severe volume overload to the left ventricle (LV) which results in dilation, eccentric hypertrophy and eventually loss of function. Little is known about the impact of AR on LV gene expression. We therefore conducted a gene expression profiling study in the LV of rats with acute and severe AR. We identified 64 genes that were specifically up-regulated and 29 that were down-regulated out of 21910 genes after 2 weeks. Of the up-regulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qPCR) to see if the modulation seen in the LV after two weeks persisted in the chronic phase (after 6 and 12 months) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are over-activated in our animal model we were interested to see if blocking those systems using metoprolol and captopril would alter the expression of some up-regulated LV genes in AR rats. By qPCR we observed that up-regulations of LV mRNA levels encoding for pro-collagens type I and III, fibronectin, atrial natriuretic peptide (ANP), transforming growth factor β2 (TGFβ2) and connective tissue growth factor (CTGF) were totally or partially reversed by a combination of metoprolol (25 mg/kg/d) and captopril (100 mg/kg/d). These observations provide a molecular rationale for a medical strategy aiming these systems in the medical treatment of AR and expand the paradigm in the study of this form of LV volume overload.
