Maturation-dependent differences in regulation of sarcoplasmic reticulum Ca(2+) ATPase in sheep myocardium in response to pressure overload: a possible mechanism for maturation-dependent systolic and diastolic dysfunction.
We have previously demonstrated that pressure-overload hypertrophy in adult sheep is associated with myocardial dysfunction whereas that in young lambs is associated with normal contractility. To probe for possible mechanisms of these age-dependent differences, we assessed mRNA expression of genes encoding critical components of myocardial Ca(2+) handling in the same animal model. We studied left ventricular myocardium of young and adult sheep with short-term (48 h) and long-term (6 wk) pressure overload induced by ascending aortic constriction. Six weeks of pressure overload induced the significant left ventricular hypertrophy (36 and 39% increase in left ventricular/body weight ratio in lambs and sheep, respectively). The Ca(2+) ATPase and Na(+)/Ca(2+) exchanger mRNA decreased with pressure overload only in the adult (p < 0.05). Ca(2+) channel mRNA was slightly increased by pressure overload regardless of age (p < 0.05). Calsequestrin, sarcoplasmic reticulum Ca(2+) release channel, or myosin heavy-chain mRNA levels did not significantly differ. In adult sheep after 6 wk of pressure overload, decreases in load-adjusted midwall shortening (systolic dysfunction) and prolongation of relaxation time constant (diastolic dysfunction) correlated with decreases in Ca(2+)-ATPase mRNA. The sarcoplasmic reticulum Ca(2+)-ATPase protein level and Ca(2+) uptake activity of isolated sarcoplasmic reticulum vesicles were depressed only in the adult with pressure-overload hypertrophy but not in the young. We demonstrated age-dependent differences in mRNA expression of Ca(2+)-handling protein genes in response to pressure overload, which preceded the occurrence of hypertrophy and myocardial dysfunction. Thus, altered expression of Ca(2+)-handling protein genes may be one of the primary responses to pressure overload rather than a phenomenon secondary to myocardial hypertrophy.
Aoyagi
T
T
Cardiovascular Division, Brigham & Women's Hospital, 330 Brookline Ave., Boston, Massachusetts 02115, U.S.A.
Fujii
A M
AM
Flanagan
M F
MF
Arnold
L
L
Mirsky
I
I
Izumo
S
S
D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D003971:Diastole / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D006321:Heart / Q000254:growth & development; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D066298:In Vitro Techniques; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D012756:Sheep; D019831:Sodium-Calcium Exchanger / Q000235:genetics / Q000378:metabolism; D013599:Systole / Q000502:physiology
D012333:RNA, Messenger; D019831:Sodium-Calcium Exchanger; D000252:Calcium-Transporting ATPases; D002118:Calcium