MacDonnell Scott M, Kubo Hajime, Harris David M, Chen Xiongwen, Berretta Remus, Barbe Mary F, Kolwicz Stephen, Reger Patricia O, Eckhart Andrea, Renna Brian F, Koch Walter J, Houser Steven R, Libonati Joseph R
Cardiovascular Research Center, Temple University, Philadelphia, PA, USA.
Am J Physiol Heart Circ Physiol. 2007 Nov;293(5):H3122-9. doi: 10.1152/ajpheart.00687.2007. Epub 2007 Sep 7.
Calcineurin, a Ca(2+)-regulated protein phosphatase, links myocardial Ca(2+) signaling with hypertrophic gene transcription. Calcineurin abundance increases in pressure-overload hypertrophy and may reduce agonist-mediated phospholamban (PLB) phosphorylation to underlie blunted beta-adrenergic receptor (beta-AR) responsiveness in hypertension. This hypothesis was tested by measuring the effects of calcineurin inhibition on changes in cardiac contractility caused by beta-adrenergic stimulation in spontaneously hypertensive rats (SHR). Female SHR (age: 7 mo) and age-matched female Wistar-Kyoto rats (WKY) were studied. Heart weight-to-body weight ratio (P < 0.01) and systolic blood pressure (P < 0.01) were greater in SHR compared with WKY and were associated with increased myocardial calcineurin mRNA (CnAbeta) and activity (P < 0.05). beta-AR stimulation with isoproterenol (Iso) increased calcineurin activity (P < 0.05) in both WKY and SHR hearts, and this activity was suppressed with cyclosporin A (CsA) treatment. In SHR, CsA improved left ventricular whole heart and isolated myocyte beta-AR responsiveness by normalizing PLB phosphorylation at Ser(16) and Thr(17) (P < 0.05). These CsA-induced, PLB-mediated effects were associated with an augmentation in cardiomyocyte peak Ca(2+) and a reduced rate (time constant of isovolumic pressure relaxation, tau) and magnitude of diastolic Ca(2+) during beta-AR stimulation. In conclusion, CsA normalized the blunted beta-AR responsiveness associated with hypertension, in part, by mitigating calcineurin activity while improving PLB phosphorylation and subsequent sarcoplasmic reticulum Ca(2+) regulation.
钙调神经磷酸酶是一种受Ca(2+)调节的蛋白磷酸酶，它将心肌Ca(2+)信号与肥厚性基因转录联系起来。在压力超负荷性肥大中，钙调神经磷酸酶的丰度增加，可能会降低激动剂介导的受磷蛋白（PLB）磷酸化，从而导致高血压患者β肾上腺素能受体（β-AR）反应性减弱。通过测量钙调神经磷酸酶抑制对自发性高血压大鼠（SHR）中β肾上腺素能刺激引起的心脏收缩性变化的影响，对这一假设进行了验证。研究了雌性SHR（年龄：7个月）和年龄匹配的雌性Wistar-Kyoto大鼠（WKY）。与WKY相比，SHR的心脏重量与体重之比（P < 0.01）和收缩压（P < 0.01）更高，且与心肌钙调神经磷酸酶mRNA（CnAbeta）和活性增加相关（P < 0.05）。用异丙肾上腺素（Iso）刺激β-AR可增加WKY和SHR心脏中的钙调神经磷酸酶活性（P < 0.05），而环孢素A（CsA）处理可抑制这种活性。在SHR中，CsA通过使Ser(16)和Thr(17)位点的PLB磷酸化正常化，改善了左心室全心和分离心肌细胞的β-AR反应性（P < 0.05）。这些CsA诱导的、PLB介导的效应与β-AR刺激期间心肌细胞Ca(2+)峰值增加以及舒张期Ca(2+)的速率（等容压力松弛时间常数，tau）和幅度降低有关。总之，CsA通过减轻钙调神经磷酸酶活性，同时改善PLB磷酸化及随后的肌浆网Ca(2+)调节，部分地使与高血压相关的β-AR反应性减弱正常化。
