title: Losartan attenuates phospholipase C isozyme gene expression in hypertrophied hearts due to volume overload.
abstract: Because the left ventricular (LV) hypertrophy due to volume overload induced by arteriovenous (AV) shunt was associated with an increase in phospholipase C (PLC) isozyme mRNA levels, PLC is considered to be involved in the development of cardiac hypertrophy. Since the renin-angiotensin system (RAS) is activated in cardiac hypertrophy, the role of RAS in the stimulation of PLC isozyme gene expression in hypertrophied heart was investigated by inducing AV shunt in Sprague-Dawley rats. The animals were treated with or without losartan (20 mg/kg, daily) for 3 days as well as 1, 2 and 4 weeks, and atria, right ventricle (RV) and LV were used for analysis. The increased muscle mass as well as the mRNA levels for PLC beta1 and beta3 in atria and RV, unlike PLC beta3 gene expression in LV, at 3 days of AVshunt were attenuated by losartan. The increased gene expression for PLC beta1 at 2 weeks in atria, at 1 and 4 weeks in RV, and at 2 and 4 weeks in LV was also depressed by losartan treatment. Likewise, the elevated mRNA levels for PLC beta3 in RV at 1 week and in LVat 4 weeks of cardiac hypertrophy were decreased by losartan. On the other hand, the increased levels of mRNA for PLC gamma1 in RV and LV at 2 and 4 weeks of inducing hypertrophy, unlike in atria at 4 weeks were not attenuated by losartan treatment. While the increased mRNA level for PLC delta1 in LV was reduced by losartan, gene expression for PLC delta1 was unaltered in atria and decreased in RV at 3 days of inducing AV shunt. These results suggest that changes in PLC isozyme gene expression were chamber specific and time-dependent upon inducing cardiac hypertrophy due to AV shunt. Furthermore, partial attenuation of the increased gene expression for some of the PLC isozymes and no effect of losartan on others indicate that both RAS dependent and independent mechanisms may be involved in hypertrophied hearts due to volume overload.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology, Faculty of Medicine, University of Manitoba Winnipeg, Canada.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Dent
authors.forename: Nina
authors.initials: N
authors.lastname: Aroutiounova
authors.forename: N S
authors.initials: NS
authors.lastname: Dhalla
authors.forename: P S
authors.initials: PS
authors.lastname: Tappia
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D015870:Gene Expression; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D010738:Type C Phospholipases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D007527:Isoenzymes; D012333:RNA, Messenger; D010738:Type C Phospholipases; D019808:Losartan