Skeletal Muscle-Specific Genetic Determinants Contribute to the Differential Strain-Dependent Effects of Hindlimb Ischemia in Mice
Skeletal Muscle-Specific Genetic Determinants Contribute to the Differential Strain-Dependent Effects of Hindlimb Ischemia in Mice
复制标题
DOI：
10.1016/j.ajpath.2012.01.032
复制
发表时间：
2012-05-01
影响因子：
6
通讯作者：
Kontos, Christopher D.
中科院分区：
文献类型：
--
作者：
McClung, Joseph M.;McCord, Timothy J.;Kontos, Christopher D.
遗传学在确定外周动脉疾病（PAD）病理学中起着重要作用，PAD病理学导致一系列临床疾病，从临床上无症状的血流减少到威胁肢体的缺血。然而，PAD病理的细胞类型特异性很少受到关注。为了确定骨骼肌细胞中的应变依赖性差异是否可以解释在C57 BL/6和BALB/c小鼠中观察到的对缺血的差异反应，将内皮细胞和骨骼肌细胞在体外进行缺氧和营养剥夺（HND）以模拟缺血。肌细胞比内皮细胞更易受HND的影响。在体内，C57 BL/6和BALB/c小鼠后肢缺血后的肌纤维反应表现出品系特异性差异，在BALB/c小鼠中，肌纤维萎缩显著更大，细胞凋亡更大，成肌调节基因表达和应激反应信号减弱。在HND后，两种菌株的原代肌细胞在体外重现了菌株特异性缺陷。C57 BL/6 Lsq-1数量性状基因座同源的BALB/c小鼠的肌细胞受到HND诱导的萎缩的保护，并且血管生长因子及其受体的基因表达在C57 BL/6原代肌细胞中显著更高。我们的研究结果表明，以前确定的特定的遗传位点调节应变依赖性侧支血管密度有一个非血管或肌细胞自主的作用，涉及生肌程序和传统的血管生长因子受体的表达。(Am J Pathol 2012，180：2156-2169; DOI：10.1016/j.ajpath.2012.01.032）
Genetics plays an important role in determining peripheral arterial disease (PAD) pathology, which causes a spectrum of clinical disorders that range from clinically silent reductions in blood flow to limb-threatening ischemia. The cell-type specificity of PAD pathology, however, has received little attention. To determine whether strain-dependent differences in skeletal muscle cells might account for the differential responses to ischemia observed in C57BL/6 and BALB/c mice, endothelial and skeletal muscle cells were subjected to hypoxia and nutrient deprivation (HND) in vitro, to mimic ischemia. Muscle cells were more susceptible to HND than were endothelial cells. In vivo, C57BL/6 and BALB/c mice displayed strain-specific differences in myofiber responses after hindlimb ischemia, with significantly greater myofiber atrophy, greater apoptosis, and attenuated myogenic regulatory gene expression and stress-responsive signaling in BALB/c mice. Strain-specific deficits were recapitulated in vitro in primary muscle cells from both strains after HND. Muscle cells from BALB/c mice congenic for the C57BL/6 Lsq-1 quantitative trait locus were protected from HND-induced atrophy, and gene expression of vascular growth factors and their receptors was significantly greater in C57BL/6 primary muscle cells. Our results indicate that the previously identified specific genetic locus regulating strain-dependent collateral vessel density has a nonvascular or muscle cell-autonomous role involving both the myogenic program and traditional vascular growth factor receptor expression. (Am J Pathol 2012, 180:2156-2169; DOI: 10.1016/j.ajpath.2012.01.032)