Bridgman Paul, Aronovitz Mark A, Kakkar Rahul, Oliverio Michael I, Coffman Thomas M, Rand William M, Konstam Marvin A, Mendelsohn Michael E, Patten Richard D
Molecular Cardiology Research Institute, Tufts-New England Medical Center, Box 80, 750 Washington St., Boston, MA 02111, USA.
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H586-92. doi: 10.1152/ajpheart.00474.2004. Epub 2005 Mar 11.
Left ventricular (LV) remodeling after myocardial infarction (MI) results from hypertrophy of myocytes and activation of fibroblasts induced, in part, by ligand stimulation of the ANG II type 1 receptor (AT1R). The purpose of the present study was to explore the specific role for activation of the AT 1a R subtype in post-MI remodeling and whether gender differences exist in the patterns of remodeling in wild-type and AT 1a R knockout (KO) mice. AT 1a R-KO mice and wild-type littermates underwent coronary ligation to induce MI or sham procedures; echocardiography and hemodynamic evaluation were performed 6 wk later, and LV tissue was harvested for infarct size determination, morphometric measurements, and gene expression analysis. Survival and infarct size were similar among all male and female wild-type and AT 1a R-KO mice. Hemodynamic indexes were also similar except for lower systolic blood pressure in the AT 1a R-KO mice compared with wild-type mice. Male and female wild-type and male AT 1a R-KO mice developed similar increases in LV chamber size, LV mass corrected for body weight (LV/BW), and myocyte cross-sectional area (CSA). However, female AT 1a R-KO mice demonstrated no increase in LV/BW and myocyte CSA post-MI compared with shams. Both male and female wild-type mice demonstrated higher atrial natriuretic peptide (ANP) levels after MI, with female wild types being significantly greater than males. However, male and female AT 1a R-KO mice developed no increase in ANP gene expression with MI despite an increase in LV mass and myocyte size in males. These data support that gender-specific patterns of LV and myocyte hypertrophy exist after MI in mice with a disrupted AT 1a R gene, and suggest that myocyte hypertrophy post-MI in females relies, in part, on activation of the AT 1a R. Further work is necessary to explore the potential mechanisms underlying these gender-based differences.
心肌梗死（MI）后左心室（LV）重塑是由心肌细胞肥大和成纤维细胞激活引起的，部分原因是血管紧张素II 1型受体（AT1R）的配体刺激。本研究的目的是探讨AT1aR亚型激活在心肌梗死后重塑中的具体作用，以及野生型和AT1aR基因敲除（KO）小鼠的重塑模式是否存在性别差异。对AT1aR-KO小鼠和野生型同窝小鼠进行冠状动脉结扎以诱导心肌梗死或假手术；6周后进行超声心动图和血流动力学评估，并采集左心室组织用于梗死面积测定、形态测量和基因表达分析。所有雄性和雌性野生型及AT1aR-KO小鼠的生存率和梗死面积相似。除了AT1aR-KO小鼠的收缩压低于野生型小鼠外，血流动力学指标也相似。雄性和雌性野生型小鼠以及雄性AT1aR-KO小鼠的左心室腔大小、校正体重后的左心室质量（LV/BW）和心肌细胞横截面积（CSA）均有相似的增加。然而，与假手术组相比，雌性AT1aR-KO小鼠在心肌梗死后LV/BW和心肌细胞CSA没有增加。雄性和雌性野生型小鼠在心肌梗死后心房利钠肽（ANP）水平均升高，雌性野生型小鼠显著高于雄性。然而，尽管雄性AT1aR-KO小鼠的左心室质量和心肌细胞大小增加，但心肌梗死后ANP基因表达并未增加。这些数据支持在AT1aR基因缺失的小鼠中，心肌梗死后存在左心室和心肌细胞肥大的性别特异性模式，并表明雌性心肌梗死后的心肌细胞肥大部分依赖于AT1aR的激活。有必要进一步研究这些基于性别的差异的潜在机制。
