Senescent heart compared with pressure overload-induced hypertrophy.
Although systolic left ventricular (LV) function is normal in the elderly, aging is associated in rat papillary muscle with mechanical and sarcoplasmic reticulum Ca2+ ATPase alterations similar to those observed in the hypertrophied heart. However, alterations in the other calcium-regulating proteins implicated in contraction and relaxation are still unknown. To investigate alterations in LV function and calcium-regulating proteins, we measured hemodynamics and Na(+)-Ca2+ exchanger (NCx), ryanodine receptor (RyR2), and sarcoplasmic reticular Ca2+ ATPase (SERCA2) mRNA levels (expressed in densitometric scores normalized to that of poly(A+) mRNA) in left ventricle from 4-month-old (adult, n = 13) and 24-month-old (senescent, n = 15) rats. For ex vivo contractile function, active tension was measured during isolated heart perfusion in adult (n = 11) and senescent (n = 11) rats. For comparison of age-dependent effects of moderate hypertension on both hemodynamics and calcium proteins, renovascular hypertension was induced or a sham operation performed at 2 (n = 11 and n = 6) and 22 (n = 26 and n = 5) months of age. In senescent rats, LV systolic pressure and maximal rates of pressure development were unaltered, although active tension was depressed (4.7 +/- 0.4 versus 8.3 +/- 0.7 g/g heart weight in adults, P < .0001). SERCA2 mRNA levels were decreased in senescent left ventricle (0.98 +/- 0.05 versus 1.18 +/- 0.05 in adults, P < .01), without changes in NCx and RyR2 mRNA accumulation. Renovascular hypertension resulted in 100% mortality in aged rats; in adults, renovascular hypertension resulted, 2 months later, in an increase of LV systolic pressure (170 +/- 7 versus 145 +/- 3 mm Hg in sham-operated rats, P < .05) and in mild LV hypertrophy (+18%, P < .01) associated with a decrease in SERCA2 mRNA levels (1.02 +/- 0.03 versus 1.18 +/- 0.03 in sham-operated rats, P < .001). Contractile dysfunction in senescent isolated heart and decreased SERCA2 mRNA levels were associated with in vivo normal LV function at rest, indicating the existence of in vivo compensatory mechanisms. RyR2 and NCx gene expressions were not implicated in the observed contractile dysfunction. In aged rats, renovascular hypertension resulted in 100% mortality, probably related to elevated levels of circulating angiotensin II, whereas in adult rats, renovascular hypertension induced a mild LV hypertrophy associated with a selective alteration in SERCA2 gene expression.
Assayag
P
P
Institut National de la Santé et de la Recherche Médicale (INSERM) U127, IFR Circulation, Hôpital Lariboisière, Paris, France.
Charlemagne
D
D
de Leiris
J
J
Boucher
F
F
Valère
P E
PE
Lortet
S
S
Swynghedauw
B
B
Besse
S
S
D000375:Aging / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure; D015152:Blotting, Northern; D015220:Calcium Channels / Q000032:analysis / Q000235:genetics; D000252:Calcium-Transporting ATPases / Q000032:analysis / Q000235:genetics; D006328:Cardiac Catheterization; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D003326:Coronary Circulation; D006321:Heart / Q000502:physiology*; D006339:Heart Rate; D006352:Heart Ventricles / Q000737:chemistry; D006978:Hypertension, Renovascular / Q000150:complications / Q000401:mortality / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009124:Muscle Proteins / Q000032:analysis / Q000235:genetics; D010477:Perfusion; D011061:Poly A / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D019831:Sodium-Calcium Exchanger; D016277:Ventricular Function, Left / Q000502:physiology*
D015220:Calcium Channels; D002352:Carrier Proteins; D009124:Muscle Proteins; D012333:RNA, Messenger; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D011061:Poly A; D000252:Calcium-Transporting ATPases