Assayag P, Charlemagne D, de Leiris J, Boucher F, Valère P E, Lortet S, Swynghedauw B, Besse S
Institut National de la Santé et de la Recherche Médicale (INSERM) U127, IFR Circulation, Hôpital Lariboisière, Paris, France.
Hypertension. 1997 Jan;29(1 Pt 1):15-21. doi: 10.1161/01.hyp.29.1.15.
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.
尽管老年人的左心室（LV）收缩功能正常，但衰老与大鼠乳头肌的机械和肌浆网Ca2+ATP酶改变有关，这些改变类似于在肥厚心脏中观察到的改变。然而，参与收缩和舒张的其他钙调节蛋白的改变仍然未知。为了研究LV功能和钙调节蛋白的改变，我们测量了4个月大（成年，n = 13）和24个月大（衰老，n = 15）大鼠左心室的血流动力学以及钠钙交换体（NCx）、兰尼碱受体（RyR2）和肌浆网Ca2+ATP酶（SERCA2）的mRNA水平（以相对于聚腺苷酸（A+）mRNA的光密度分数表示）。对于离体收缩功能，在成年（n = 11）和衰老（n = 11）大鼠的离体心脏灌注期间测量主动张力。为了比较中度高血压对血流动力学和钙蛋白的年龄依赖性影响，在2个月（n = 11和n = 6）和22个月（n = 并26和n = 5）时诱导肾血管性高血压或进行假手术。在衰老大鼠中，LV收缩压和最大压力上升速率未改变，尽管主动张力降低（成年大鼠为4.7±0.4对8.3±0.7 g/g心脏重量，P <.0001）。衰老左心室中SERCA2 mRNA水平降低（成年大鼠为0.98±0.05对1.18±0.05，P <.01），而NCx和RyR2 mRNA积累无变化。肾血管性高血压导致老年大鼠100%死亡；在成年大鼠中，肾血管性高血压在2个月后导致LV收缩压升高（假手术大鼠为170±7对145±3 mmHg，P <.05）和轻度LV肥厚（+18%，P <.01），同时SERCA2 mRNA水平降低（假手术大鼠为1.02±0.03对1.18±0.03，P <.001）。衰老离体心脏的收缩功能障碍和SERCA2 mRNA水平降低与静息时体内正常的LV功能相关，表明存在体内代偿机制。RyR2和NCx基因表达与观察到的收缩功能障碍无关。在老年大鼠中，肾血管性高血压导致100%死亡，可能与循环中血管紧张素II水平升高有关，而在成年大鼠中，肾血管性高血压诱导轻度LV肥厚，伴有SERCA2基因表达的选择性改变。
