Gene profiling of left ventricle eccentric hypertrophy in aortic regurgitation in rats: rationale for targeting the beta-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 upregulated and 29 that were downregulated out of 21,910 genes after 2 wk. Of the upregulated genes, a good proportion was related to the extracellular matrix. We subsequently studied a subset of 19 genes by quantitative RT-PCR (qRT-PCR) to see if the modulation seen in the LV after 2 wk persisted in the chronic phase (after 6 and 12 mo) and found that it did persist. Knowing that the adrenergic and renin-angiotensin systems are overactivated in our animal model, we were interested to see if blocking those systems using metoprolol (25 mg.kg(-1).day(-1)) and captopril (100 mg.kg(-1).day(-1)) would alter the expression of some upregulated LV genes in AR rats after 6 mo. By qRT-PCR, we observed that upregulations of LV mRNA levels encoding for procollagens type I and III, fibronectin, atrial natriuretic peptide, transforming growth factor-beta(2), and connective tissue growth factor were totally or partially reversed by this treatment. 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.
Champetier
Serge
S
Groupe de Recherche en Valvulopathies, Centre de Recherche Hôpital Laval, 2725, Chemin Sainte-Foy, Québec, Québec, Canada G1V 4G5.
Bojmehrani
Azadeh
A
Beaudoin
Jonathan
J
Lachance
Dominic
D
Plante
Eric
E
Roussel
Elise
E
Couet
Jacques
J
Arsenault
Marie
M
D000208:Acute Disease; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index; D013997:Time Factors
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D002216:Captopril; D008790:Metoprolol