McConnell B K, Moravec C S, Bond M
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland 44106, USA.
Am J Physiol. 1998 Feb;274(2):H385-96. doi: 10.1152/ajpheart.1998.274.2.H385.
We have measured myocyte cell shortening, troponin-I (Tn-I) phosphorylation, Ca2+ dependence of actomyosin adenosinetriphosphatase (ATPase) activity, adenosine 3',5'-cyclic monophosphate (cAMP) levels, and myofibrillar isoform expression in the spontaneously hypertensive rat (SHR) during decompensated cardiac hypertrophy (76 wk old) and in age-matched Wistar-Kyoto rat (WKY) controls. The decreased inotropic response to beta-adrenergic stimulation previously observed in myocytes from 26-wk-old SHR was further reduced at 76 wk of age. In response to beta-adrenergic stimulation, Tn-I phosphorylation was greater in the 76-wk-old SHR than in the WKY, although cAMP-dependent protein kinase A (PKA)-dependent Tn-I phosphorylation in the SHR did not increase with progression from compensated (26 wk) to decompensated (76 wk) hypertrophy. We also observed a dissociation between the increased PKA-dependent Tn-I phosphorylation and decreased cAMP levels in the 76-wk-old SHR versus WKY during beta-adrenergic stimulation. Baseline Tn-I phosphorylation was significantly reduced in 76-wk-old SHR versus WKY and was associated with decreased basal cAMP levels and increased Ca2+ sensitivity of actomyosin ATPase activity. The change in myofilament Ca2+ sensitivity during beta-adrenergic stimulation in the 76-wk-old SHR (0.65 pCa units) was over twofold greater than in the 76-wk-old WKY (0.30 pCa units). We also determined whether embryonic troponin T isoforms were reexpressed in decompensated hypertrophy and observed significant reexpression of the embryonic cardiac troponin T isoforms in the 76-wk-old SHR. The significant decrease in Ca2+ sensitivity with beta-adrenergic stimulation in 76-wk-old SHR may contribute to the severely impaired inotropic response during decompensated hypertrophy in the SHR.
我们测量了失代偿性心肌肥厚（76周龄）的自发性高血压大鼠（SHR）以及年龄匹配的Wistar-Kyoto大鼠（WKY）对照组的心肌细胞缩短、肌钙蛋白I（Tn-I）磷酸化、肌动球蛋白三磷酸腺苷酶（ATPase）活性的钙依赖性、环磷酸腺苷（cAMP）水平和肌原纤维亚型表达。先前在26周龄SHR的心肌细胞中观察到的对β-肾上腺素能刺激的变力反应降低，在76周龄时进一步降低。在β-肾上腺素能刺激下，76周龄SHR的Tn-I磷酸化比WKY更明显，尽管SHR中cAMP依赖性蛋白激酶A（PKA）依赖性Tn-I磷酸化并未随着从代偿性（26周）到失代偿性（76周）肥厚的进展而增加。我们还观察到，在β-肾上腺素能刺激期间，76周龄SHR与WKY相比，PKA依赖性Tn-I磷酸化增加与cAMP水平降低之间存在分离。与WKY相比，76周龄SHR的基线Tn-I磷酸化显著降低，并且与基础cAMP水平降低和肌动球蛋白ATPase活性的钙敏感性增加有关。76周龄SHR在β-肾上腺素能刺激期间肌丝钙敏感性的变化（0.65 pCa单位）比76周龄WKY（0.30 pCa单位）大两倍多。我们还确定了胚胎肌钙蛋白T亚型在失代偿性肥厚中是否重新表达，并观察到76周龄SHR中胚胎心肌肌钙蛋白T亚型有显著重新表达。76周龄SHR在β-肾上腺素能刺激下钙敏感性的显著降低可能导致SHR失代偿性肥厚期间变力反应严重受损。
