Pressure overload-induced alterations in fibrillar collagen content and myocardial diastolic function: role of secreted protein acidic and rich in cysteine (SPARC) in post-synthetic procollagen processing.
Pressure overload-induced alterations in fibrillar collagen content and myocardial diastolic function: role of secreted protein acidic and rich in cysteine (SPARC) in post-synthetic procollagen processing.
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DOI：
10.1161/circulationaha.108.773424
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发表时间：
2009-01-20
期刊：
影响因子：
37.8
通讯作者：
Zile MR
中科院分区：
文献类型：
--
作者：
Bradshaw AD;Baicu CF;Rentz TJ;Van Laer AO;Boggs J;Lacy JM;Zile MR
慢性压力超负荷（PO）导致心肌肥厚、纤维胶原含量增加和舒张功能异常。我们假设这些PO诱导的变化的一个决定因素是新合成的前胶原到成熟的胶原纤维的细胞外加工。我们进一步假设，在正常和PO心肌中，酸性和富含半胱氨酸的分泌蛋白（Secreted Protein Acidic and Rich in Cysteine）在合成后前胶原加工中起关键作用。为了确定PO诱导的胶原蛋白含量和舒张功能的变化是否受到没有ESTA的影响，年龄匹配的野生型（WT）和ESTA无效小鼠经历4周的横向主动脉缩窄（TAC）或作为非手术对照（对照）。通过胶原体积分数（CVF）在组织学上测量左心室（LV）胶原含量，通过羟脯氨酸测定法测量可溶性胶原（1 M NaCl可提取物）与不溶性胶原（成熟交联）的胶原组成，并通过扫描电子显微镜检查胶原形态结构。通过免疫印迹法测量β-淀粉样蛋白表达。采用超声心动图、乳头肌和离体心肌细胞研究评估LV、心肌和心肌细胞的结构和功能。在WT小鼠中，TAC增加了LV质量、心肌肥厚表达、心肌舒张僵硬度、纤维胶原含量、可溶性和不溶性胶原。在TBI基因敲除小鼠中，TAC增加LV质量的程度与WT小鼠相似。此外，在TACs小鼠中，TAC增加了纤维状胶原蛋白含量，但显著低于WT TAC小鼠中所见。此外，与WT TAC小鼠相比，在野生型TAC小鼠中LV胶原不溶的比例（86± 2（99± 2%，p < 0.05），并且与WT TAC小鼠相比，在野生型TAC小鼠中可溶性胶原的比例（14±2%）更大（1± 2%，p < 0.05）结果，在野生型TAC小鼠中心肌舒张刚度（0.075±0.005）低于野生型TAC小鼠（0.045±0.005，p < 0.05）。不存在P2 O3降低了PO诱导的ECM纤维胶原和舒张功能的改变。这些数据支持了这一假设，即在正常和压力超负荷心肌中，β-淀粉样蛋白在合成后前胶原加工和成熟交联胶原纤维的形成中起关键作用。
Chronic pressure-overload (PO) causes myocardial hypertrophy, increased fibrillar collagen content, and abnormal diastolic function. We hypothesized that one determinant of these PO-induced changes is the extracellular processing of newly synthesized procollagen into mature collagen fibrils. We further hypothesized that SPARC (Secreted Protein Acidic and Rich in Cysteine) plays a key role in post-synthetic procollagen processing in normal and PO myocardium. To determine whether PO-induced changes in collagen content and diastolic function are affected by the absence of SPARC, age-matched wild-type (WT) and SPARC null mice underwent either transverse aortic constriction (TAC) for 4 weeks or served as non-operated controls (Control). Left ventricular (LV) collagen content was measured histologically by collagen volume fraction (CVF), collagen composition was measured by hydroxyproline assay as soluble collagen (1M NaCl extractable) vs. insoluble collagen (mature cross-linked), and collagen morphologic structure was examined by scanning electron microscopy. SPARC expression was measured by immunoblot. LV, myocardial, and cardiomyocyte structure and function were assessed using echocardiographic, papillary muscle and isolated cardiomyocyte studies. In WT mice, TAC increased LV mass, SPARC expression, myocardial diastolic stiffness, fibrillar collagen content, soluble, and insoluble collagen. In SPARC null mice, TAC increased LV mass to an extent similar to WT mice. In addition, in SPARC Null mice TAC increased fibrillar collagen content but significantly less than that seen in WT TAC mice. Furthermore, the proportion of LV collagen which was insoluble was less in the SPARC Null TAC mice (86±2%) compared with the WT TAC mice (99±2%, p < 0.05) and the proportion of collagen which was soluble was greater in the SPARC Null TAC mice (14±2%) compared with the WT TAC mice (1±2%, p < 0.05) As a result, myocardial diastolic stiffness was lower in the SPARC Null TAC mice (0.075±0.005) then in WT TAC mice (0.045±0.005, p < 0.05). The absence of SPARC reduced PO-induced alterations in ECM fibrillar collagen and diastolic function. These data support the hypothesis that SPARC plays a key role in post-synthetic procollagen processing and the development of mature cross-linked collagen fibrils in normal and pressure-overloaded myocardium.