title: Overexpression of type 1 angiotensin II receptors impairs excitation-contraction coupling in the mouse heart.
abstract: Transgenic mice that overexpress human type 1 angiotensin II receptor (AT(1)R) in the heart develop cardiac hypertrophy. Previously, we have shown that in 6-mo AT(1)R mice, which exhibit significant cardiac remodeling, fractional shortening is decreased. However, it is not clear whether altered contractility is attributable to AT(1)R overexpression or is secondary to cardiac hypertrophy/remodeling. Thus the present study characterized the effects of AT(1)R overexpression on ventricular L-type Ca(2+) currents (I(CaL)), cell shortening, and Ca(2+) handling in 50-day and 6-mo-old male AT(1)R mice. Echocardiography showed there was no evidence of cardiac hypertrophy in 50-day AT(1)R mice but that fractional shortening was decreased. Cellular experiments showed that cell shortening, I(CaL), and Ca(v)1.2 mRNA expression were significantly reduced in 50-day and 6-mo-old AT(1)R mice compared with controls. In addition, Ca(2+) transients and caffeine-induced Ca(2+) transients were reduced whereas the time to 90% Ca(2+) transient decay was prolonged in both age groups of AT(1)R mice. Western blot analysis revealed that sarcoplasmic reticulum Ca(2+)-ATPase and Na(+)/Ca(2+) exchanger protein expression was significantly decreased in 50-day and 6-mo AT(1)R mice. Overall, the data show that cardiac contractility and the mechanisms that underlie excitation-contraction coupling are altered in AT(1)R mice. Furthermore, since the alterations in contractility occur before the development of cardiac hypertrophy, it is likely that these changes are attributable to the increased activity of the renin-angiotensin system brought about by AT(1)R overexpression. Thus it is possible that AT(1)R blockade may help maintain cardiac contractility in individuals with heart disease.
authors.affiliation: Research Center, Montreal Heart Institute, Montreal, Québec, Canada.
authors.forename: Katy
authors.initials: K
authors.lastname: Rivard
authors.forename: Scott A
authors.initials: SA
authors.lastname: Grandy
authors.forename: Annie
authors.initials: A
authors.lastname: Douillette
authors.forename: Pierre
authors.initials: P
authors.lastname: Paradis
authors.forename: Mona
authors.initials: M
authors.lastname: Nemer
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Allen
authors.forename: Céline
authors.initials: C
authors.lastname: Fiset
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D015153:Blotting, Western; D002110:Caffeine / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D056966:Excitation Contraction Coupling / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: C544065:AGTR1 protein, human; D020746:Calcium Channels, L-Type; D044140:Receptor, Angiotensin, Type 1; D019831:Sodium-Calcium Exchanger; D002110:Caffeine; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases