Bailey Michael, Pillarisetti Swadeep, Jones Peter, Xiao Hui, Simionescu Dan, Vyavahare Narendra
501-1 Rhodes Research Center, Department of Bioengineering, Clemson University, Clemson, SC 29634, USA.
Cardiovasc Pathol. 2004 May-Jun;13(3):146-55. doi: 10.1016/S1054-8807(04)00009-2.
Elastin degeneration and calcification occur in many cardiovascular diseases, including medial arterial elastocalcinosis, atherosclerosis, and bioprosthetic heart valve mineralization. In the present study, we tested the hypothesis that the onset and progression of elastin-oriented calcification is associated with matrix remodeling and elastin degradation events. We studied whether aluminum ions inhibit elastin calcification by reducing elastin degradation and altering remodeling events. Subdermal implantation of pure elastin in juvenile rats resulted in a time-dependent calcification of elastin, reaching high levels 21 days after implantation. In situ hybridization showed that elastin calcification was associated with an up-regulation of matrix metalloproteinase (MMP) mRNA expression, specifically MMP-9 and MMP-2. Gelatin zymography demonstrated increased MMP-9 and MMP-2 enzyme activities in early stages of elastin calcification. Calcified elastin displayed a time-dependent pattern of tenascin-C (TN-C) and alkaline phosphatase (AP) expression. Pretreatment of pure elastin with aluminum ions prior to implantation resulted in complete inhibition of elastin calcification. Aluminum ion binding to elastin was found to protect elastin against MMP-mediated degradation in vitro. Noncalcified, explanted aluminum-pretreated elastin exhibited reduced activities of MMPs. TN-C expression in elastin implants exhibited a time-dependent pattern that was also affected by pretreatment of elastin with aluminum ions. In conclusion, elastin calcification is accompanied by matrix remodeling events, and the efficacy of aluminum pretreatment in inhibiting elastin calcification may be related in part to its effects on elastin remodeling.
弹性蛋白变性和钙化发生在许多心血管疾病中，包括动脉中层弹性钙化、动脉粥样硬化和生物人工心脏瓣膜矿化。在本研究中，我们验证了以下假设：以弹性蛋白为导向的钙化的发生和进展与基质重塑和弹性蛋白降解事件有关。我们研究了铝离子是否通过减少弹性蛋白降解和改变重塑事件来抑制弹性蛋白钙化。在幼年大鼠皮下植入纯弹性蛋白会导致弹性蛋白随时间发生钙化，植入后21天达到高水平。原位杂交显示，弹性蛋白钙化与基质金属蛋白酶（MMP）mRNA表达上调有关，特别是MMP-9和MMP-2。明胶酶谱分析表明，在弹性蛋白钙化的早期阶段，MMP-9和MMP-2酶活性增加。钙化的弹性蛋白呈现出肌腱蛋白-C（TN-C）和碱性磷酸酶（AP）表达的时间依赖性模式。植入前用铝离子预处理纯弹性蛋白可完全抑制弹性蛋白钙化。发现铝离子与弹性蛋白结合可在体外保护弹性蛋白免受MMP介导的降解。未钙化的、取出的经铝预处理的弹性蛋白显示出MMP活性降低。弹性蛋白植入物中的TN-C表达呈现出时间依赖性模式，这也受到用铝离子预处理弹性蛋白的影响。总之，弹性蛋白钙化伴随着基质重塑事件，铝预处理抑制弹性蛋白钙化的功效可能部分与其对弹性蛋白重塑的影响有关。
