Rodriguez Walter E, Tyagi Neetu, Deng Alan Y, Adeagbo Aso, Joshua Irving G, Tyagi Suresh C
Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, KY 40202, USA.
Arch Physiol Biochem. 2008 Dec;114(5):340-8. doi: 10.1080/13813450802535978.
Although congenic translocation of a segment from chromosome 10 from Lewis rat, containing an extracellular proteinase inhibitor gene, decreased blood pressure in Dahl-salt sensitive (DSS) rats, the relationship between the levels of matrix metalloproteinase (MMP), tissue inhibitor of metalloproteinase (TIMP), and cardiac function was unclear. In this study we investigated the cardiac effects of congenic translocation of a segment from chromosome 10 from Lewis rat, containing an extracellular proteinase inhibitor gene, in Dahl-salt sensitive rats. To test the hypothesis that left ventricular (LV) hypertrophy in DSS rats was due to high MMP and low TIMP levels and the decrease in blood pressure in congenic rats was associated with increase in proteinase inhibitor expression, cardiac function and levels of MMP and TIMP were determined in 16 weeks male DSS (D), Lewis (L) and congenic (CL-10) rats. Cardiac function was assessed by electrocardiography, echocardiography and a Millar catheter in LV cavity. LV MMP and TIMP levels were measured by Q-RT-PCR and Western blot analyses. In L, D and CL-10 rats, heart weight/body weight (g/g) were 3.73 +/- 0.06, 4.45 +/- 0.04 and 3.35 +/- 0.05 x 10(-3), respectively, suggesting significant (p < 0.05) LV hypertrophy (LVH) in D group. The ST duration was longer in D group compared with L group, suggesting coronary vasospasm, but normalized in CL-10 rats. The fractional shortening and ejection fraction were decreased in D group as compared with L group, but normalized in CL-10 groups. LV diameter was increased in D group as compared to L group, but normalized in CL-10 groups. The levels of MMP-9 were higher and TIMP were lower in D as compared to L groups, but normalized in CL-10 rats. Compared with control non-congenic Dahl rats, congenic rats exhibited lower blood pressure, amelioration of LV remodelling and dysfunction, as well as coronary abnormalities. In addition, congenic animals exhibited reduced myocardial expression of MMP-9, but increased expression of MMP-2 and TIMP-4 compared to non congenic animals. We concluded that the congenic transfer of TIMP ameliorated LV hypertrophy and cardiac dysfunction.
尽管将含有细胞外蛋白酶抑制剂基因的10号染色体片段从Lewis大鼠进行同基因易位，可降低Dahl盐敏感（DSS）大鼠的血压，但基质金属蛋白酶（MMP）、金属蛋白酶组织抑制剂（TIMP）水平与心脏功能之间的关系尚不清楚。在本研究中，我们调查了将含有细胞外蛋白酶抑制剂基因的10号染色体片段从Lewis大鼠进行同基因易位对Dahl盐敏感大鼠心脏的影响。为了验证DSS大鼠左心室（LV）肥厚是由于MMP水平高和TIMP水平低，以及同基因大鼠血压降低与蛋白酶抑制剂表达增加有关这一假设，我们测定了16周龄雄性DSS（D）、Lewis（L）和同基因（CL-10）大鼠的心脏功能以及MMP和TIMP水平。通过心电图、超声心动图和左心室腔内置入的Millar导管评估心脏功能。通过Q-RT-PCR和蛋白质印迹分析测量左心室MMP和TIMP水平。在L、D和CL-10大鼠中，心脏重量/体重（g/g）分别为3.73±0.06、4.45±0.04和3.35±0.05×10⁻³，表明D组存在显著（p<0.05）的左心室肥厚（LVH）。与L组相比，D组的ST段持续时间更长，提示冠状动脉痉挛，但在CL-10大鼠中恢复正常。与L组相比，D组的缩短分数和射血分数降低，但在CL-10组中恢复正常。与L组相比，D组的左心室直径增加，但在CL-10组中恢复正常。与L组相比，D组的MMP-9水平更高，TIMP水平更低，但在CL-10大鼠中恢复正常。与对照非同基因Dahl大鼠相比，同基因大鼠表现出更低的血压、左心室重构和功能障碍的改善以及冠状动脉异常。此外，与非同基因动物相比，同基因动物的心肌MMP-9表达降低，但MMP-2和TIMP-4表达增加。我们得出结论，TIMP的同基因转移改善了左心室肥厚和心脏功能障碍。
