Krishnamurthy Prasanna, Subramanian Venkateswaran, Singh Mahipal, Singh Krishna
Department of Physiology, James H. Quillen College of Medicine, James H. Quillen Veterans Affairs Medical Center, East Tennessee State University, Johnson City, 37614, USA.
Hypertension. 2007 Apr;49(4):865-72. doi: 10.1161/01.HYP.0000258703.36986.13. Epub 2007 Feb 5.
Sympathetic nerve activity increases in the heart during cardiac failure. Here, we hypothesized that beta1 integrins play a protective role in chronic beta-adrenergic receptor-stimulated cardiac myocyte apoptosis and heart failure. L-isoproterenol (iso; 400 microg/kg per hour) was infused in a group of wild-type (WT) and beta1 integrin heterozygous knockout (hKO) mice. Left ventricular structural and functional remodeling was studied at 7 and 28 days of iso-infusion. Western blot analysis demonstrated reduced beta1 integrin levels in the myocardium of hKO-sham. Iso-infusion increased heart weight:body weight ratios in both groups. However, the increase was significantly higher in WT-iso. M-mode echocardiography indicated increased left ventricular end-diastolic diameter, percentage of fractional shortening, and ejection fraction in the WT-iso group. The percentage of fractional shortening and ejection fraction were significantly lower in hKO-iso versus hKO-sham and WT-iso. Peak left ventricular developed pressure and left ventricular end-diastolic pressure measured using Langendorff-perfusion analyses were significantly higher in the WT-iso group (P<0.05 versus WT-sham and hKO-Iso). The number of TUNEL-positive myocytes was significantly higher in hKO-iso hearts 7 and 28 days after iso-infusion. The increase in myocyte cross-sectional area and fibrosis was higher in the WT-iso group. Matrix metalloproteinase-9 protein levels were significantly higher in WT-iso, whereas matrix metalloproteinase-2 levels were increased in hKO-iso hearts. Iso-infusion increased phosphorylation of c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in both groups. The increase in c-Jun N-terminal kinase phosphorylation was significantly higher in hKO-iso (P<0.001 versus WT-iso). Thus, beta1 integrins play a crucial role in beta-adrenergic receptor-stimulated myocardial remodeling with effects on cardiac myocyte hypertrophy, apoptosis, and left ventricular function.
心力衰竭时心脏交感神经活动增强。在此，我们假设β1整合素在慢性β-肾上腺素能受体刺激引起的心肌细胞凋亡和心力衰竭中起保护作用。对一组野生型（WT）和β1整合素杂合敲除（hKO）小鼠输注L-异丙肾上腺素（异丙肾上腺素；每小时400μg/kg）。在输注异丙肾上腺素7天和28天时研究左心室结构和功能重塑。蛋白质免疫印迹分析显示hKO-假手术组心肌中β1整合素水平降低。输注异丙肾上腺素使两组心脏重量与体重之比均增加。然而，WT-异丙肾上腺素组的增加幅度明显更高。M型超声心动图显示WT-异丙肾上腺素组左心室舒张末期内径增加、缩短分数百分比和射血分数增加。hKO-异丙肾上腺素组的缩短分数百分比和射血分数显著低于hKO-假手术组和WT-异丙肾上腺素组。使用Langendorff灌注分析测量的左心室最大发展压和左心室舒张末期压力在WT-异丙肾上腺素组显著更高（与WT-假手术组和hKO-异丙肾上腺素组相比，P<0.05）。输注异丙肾上腺素7天和28天后，hKO-异丙肾上腺素组心脏中TUNEL阳性心肌细胞数量显著更高。WT-异丙肾上腺素组心肌细胞横截面积增加和纤维化程度更高。WT-异丙肾上腺素组基质金属蛋白酶-9蛋白水平显著更高，而hKO-异丙肾上腺素组心脏中基质金属蛋白酶-2水平升高。输注异丙肾上腺素使两组c-Jun氨基末端激酶和细胞外信号调节激酶1/2磷酸化增加。hKO-异丙肾上腺素组c-Jun氨基末端激酶磷酸化增加幅度显著更高（与WT-异丙肾上腺素组相比，P<0.001）。因此，β1整合素在β-肾上腺素能受体刺激引起的心肌重塑中起关键作用，对心肌细胞肥大、凋亡和左心室功能产生影响。
