Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Am J Physiol Heart Circ Physiol. 2010 Feb;298(2):H614-22. doi: 10.1152/ajpheart.00474.2009. Epub 2009 Dec 11.
Advanced age, independent of concurrent cardiovascular disease, can be associated with increased extracellular matrix (ECM) fibrillar collagen content and abnormal diastolic function. However, the mechanisms causing this left ventricular (LV) remodeling remain incompletely defined. We hypothesized that one determinant of age-dependent remodeling is a change in the extent to which newly synthesized procollagen is processed into mature collagen fibrils. We further hypothesized that secreted protein acidic and rich in cysteine (SPARC) plays a key role in the changes in post-synthetic procollagen processing that occur in the aged myocardium. Young (3 mo old) and old (18-24 mo old) wild-type (WT) and SPARC-null mice were studied. LV collagen content was measured histologically by collagen volume fraction, collagen composition was measured by hydroxyproline assay as soluble collagen (1 M NaCl extractable) versus insoluble collagen (mature cross-linked), and collagen morphological structure was examined by scanning electron microscopy. SPARC expression was measured by immunoblot analysis. LV and myocardial structure and function were assessed using echocardiographic and papillary muscle experiments. In WT mice, advanced age increased SPARC expression, myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen. In SPARC-null mice, advanced age also increased myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen but significantly less than those seen in WT old mice. As a result, insoluble collagen and myocardial diastolic stiffness were lower in old SPARC-null mice (1.36 +/- 0.08 mg hydroxyproline/g dry wt and 0.04 +/- 0.005) than in old WT mice (1.70 +/- 0.10 mg hydroxyproline/g dry wt and 0.07 +/- 0.005, P < 0.05). In conclusion, the absence of SPARC reduced age-dependent 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 contributes to the increase in collagen content found in the aged myocardium.
高龄，与并发心血管疾病无关，可导致细胞外基质（ECM）纤维状胶原蛋白含量增加和舒张功能异常。然而，导致这种左心室（LV）重构的机制仍不完全明确。我们假设，决定年龄依赖性重构的一个因素是新合成的前胶原转化为成熟胶原纤维的程度的变化。我们进一步假设，富含半胱氨酸的酸性分泌蛋白（SPARC）在衰老心肌中发生的前胶原合成后处理的变化中起关键作用。年轻（3 个月大）和年老（18-24 个月大）的野生型（WT）和 SPARC 缺失小鼠进行了研究。通过胶原容积分数测量组织学上的 LV 胶原含量，通过羟脯氨酸测定法测量胶原组成，可溶性胶原（1 M NaCl 可提取）与不溶性胶原（成熟交联），通过扫描电子显微镜检查胶原形态结构。通过免疫印迹分析测量 SPARC 表达。使用超声心动图和乳头肌实验评估 LV 和心肌结构和功能。在 WT 小鼠中，高龄增加了 SPARC 表达、心肌舒张僵硬、纤维状胶原蛋白含量和不溶性胶原蛋白。在 SPARC 缺失的小鼠中，高龄也增加了心肌舒张僵硬、纤维状胶原蛋白含量和不溶性胶原蛋白，但明显低于 WT 老年小鼠。结果，老年 SPARC 缺失小鼠的不溶性胶原蛋白和心肌舒张僵硬（1.36 +/- 0.08 mg 羟脯氨酸/g 干重和 0.04 +/- 0.005）低于老年 WT 小鼠（1.70 +/- 0.10 mg 羟脯氨酸/g 干重和 0.07 +/- 0.005，P < 0.05）。总之，SPARC 的缺失减少了 ECM 纤维状胶原蛋白和舒张功能随年龄的变化。这些数据支持 SPARC 在合成后前胶原处理中起关键作用并导致衰老心肌中胶原蛋白含量增加的假设。
