Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103, USA.
Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1614-24. doi: 10.1152/ajpheart.01072.2011. Epub 2012 Feb 3.
We examined α(1A)-adrenergic receptor (AR) mediation of preconditioning in a novel α(1A)-AR cardiac transgenic (TG) rat model (α(1A)-TG). Compared with nontransgenic littermates (NTLs), in conscious α(1A)-TG rats, heart rate was reduced, contractility [left ventricle (LV) +dP/dt, ejection fraction, end-systolic elastance] was significantly enhanced, and triple product (LV systolic wall stress × LV +dP/dt × heart rate) was unchanged. However, infarct size (IS)/area at risk (AAR) in response to ischemia-reperfusion (30 min coronary occlusion/3 h reperfusion) was reduced to 35 ± 4.6% in α(1A)-TGs vs. 52 ± 2.2% in NTLs (P < 0.05). Second window preconditioning reduced IS/AAR in NTLs to 29 ± 2.7% but did not afford further protection in α(1A)-TGs. In contrast, with first window preconditioning, IS/AAR was reduced to similar levels in both α(1A)-TGs (12 ± 1.4%) and NTLs (10 ± 1.1%). In untreated α(1A)-TGs, cardioprotection was associated with enhanced myocardial phosphorylated (p)-mitogen/extracellular signal-regulated kinase (MEK), p-extracellular signal-regulated kinase (ERK), and inducible nitric oxide synthase (iNOS) at the protein level, along with a 1.3-fold increase in total nitric oxide synthase activity like in second window preconditioning. Affymetrix microarrays revealed that few genes (4.6% of 3,172 upregulated; 8.8% of 3,498 downregulated) showed directionally similar changes in α(1A)-TGs vs. NTLs subjected to second window preconditioning. Thus, second, but not first, window cardioprotection is evident in α(1A)-TGs in the absence of ischemic preconditioning and is mediated by iNOS activation associated with MEK/ERK phosphorylation. Transcriptionally, however, second window preconditioning is considerably more complex than α(1A)-TG preconditioning, with the alteration of thousands of additional genes affording no further protection than that already available in α(1A)-TG rats.
我们在一种新的α(1A)-肾上腺素能受体（AR）心脏转基因（TG）大鼠模型（α(1A)-TG）中研究了α(1A)-AR 预处理的介导作用。与非转基因同窝仔（NTL）相比，在清醒的α(1A)-TG 大鼠中，心率降低，收缩性[左心室（LV）+dP/dt、射血分数、收缩末期弹性]显著增强，三乘积（LV 收缩壁应力×LV+dP/dt×心率）不变。然而，缺血再灌注（30 分钟冠状动脉闭塞/3 小时再灌注）引起的梗死面积（IS）/危险区（AAR）在α(1A)-TG 中降至 35±4.6%，而在 NTL 中降至 52±2.2%（P<0.05）。第二窗口预处理使 NTL 的 IS/AAR 降低至 29±2.7%，但在α(1A)-TG 中不能提供进一步的保护。相比之下，用第一窗口预处理，IS/AAR 在α(1A)-TG（12±1.4%）和 NTL（10±1.1%）中降低到相似水平。在未经处理的α(1A)-TG 中，心肌保护与蛋白水平上的磷酸化（p）-有丝分裂原/细胞外信号调节激酶（MEK）、p-细胞外信号调节激酶（ERK）和诱导型一氧化氮合酶（iNOS）的增强有关，并且总一氧化氮合酶活性增加了 1.3 倍，类似于第二窗口预处理。Affymetrix 微阵列显示，在第二窗口预处理的α(1A)-TG 中，只有少数基因（3172 个上调基因的 4.6%；3498 个下调基因的 8.8%）表现出与 NTL 方向相似的变化。因此，第二但不是第一窗口的心肌保护在没有缺血预处理的情况下在α(1A)-TG 中是明显的，并且由 iNOS 激活介导，与 MEK/ERK 磷酸化有关。然而，转录上，第二窗口预处理比α(1A)-TG 预处理复杂得多，数千个额外基因的改变提供的保护并不比α(1A)-TG 大鼠中已经存在的保护更好。
