Anger Thomas, Carson Walter, Weyand Michael, Daniel Werner G, Hoeher Martin, Garlichs Christoph D
Department of Cardiology, Friedrich-Alexander University of Erlangen, Germany.
Exp Mol Pathol. 2009 Feb;86(1):10-7. doi: 10.1016/j.yexmp.2008.11.001. Epub 2008 Nov 19.
Sclerotic calcification of the aortic valve is a common disease in advanced age. However, pathophysiologic processes leading to valve calcifications are poorly understood. Transformation of atherosclerotic triggers to osteogenic differentiation is controversially discussed and is thought as a trigger of bone transformation in end stage disease. This study focuses on the transcriptional gene-profiling of severe calcified stenotic human aortic valves to clarify the molecular basis of the pathophysiological process. We collected severely calcified and stenotic human aortic valves (CSAV) with (CSAV+, n=10) and without (CSAV-, n=10) at least 4 weeks of statin pre-treatment prior to valve replacement and investigated transcriptional steady-state gene-profiling by using micro array technique and GAPDH-adjusted PCR for confirmation. Results were compared with findings in non-sclerotic aortic valves: C (n=6). Various parameters of inflammation were significantly up regulated as compared to C: eotaxin3, monokine induced by gamma-interferon, vascular adhesion protein-1 (VAP-1), peroxisome proliferative activated receptor-alpha or transforming growth factor beta 1 (TGF beta 1). Except for TGF beta 1 and VAP-1, statin pre-treatment neutralized altered gene expression. Genes of osteogenic bone transformation (tenascin C, bone sialoprotein, Cbfa1, Osteocalcin, Beta-catenin, Sox- and Cyclin-genes) were found unaltered in their expression in both, CSAV- or CSAV+ in comparison to C. This study shows continuing atherosclerotic inflammation on CSAV. Additionally, no evidence of initiated osteoblastic differentiation process was found. Pre-treatment of patients with statins partially neutralized the gene pattern of inflammation on the aortic valves. This suggests that there are potent benefits of statins on early development of inflammation on calcified aortic valves.
主动脉瓣硬化钙化是老年人的常见疾病。然而，导致瓣膜钙化的病理生理过程仍知之甚少。动脉粥样硬化触发因素向成骨分化的转变存在争议，被认为是终末期疾病骨转化的触发因素。本研究聚焦于重度钙化狭窄的人主动脉瓣的转录基因谱分析，以阐明病理生理过程的分子基础。我们收集了重度钙化狭窄的人主动脉瓣（CSAV），其中接受他汀类药物预处理至少4周后进行瓣膜置换的（CSAV+，n = 10）和未接受预处理的（CSAV-，n = 10），并使用微阵列技术和GAPDH校正的PCR进行转录稳态基因谱分析以进行验证。将结果与非硬化主动脉瓣（C，n = 6）的结果进行比较。与C组相比，各种炎症参数显著上调：嗜酸性粒细胞趋化因子3、γ干扰素诱导的单核因子、血管粘附蛋白-1（VAP-1）、过氧化物酶体增殖物激活受体-α或转化生长因子β1（TGFβ1）。除了TGFβ1和VAP-1，他汀类药物预处理可中和基因表达的改变。与C组相比，成骨骨转化相关基因（腱生蛋白C、骨唾液蛋白、Cbfa1、骨钙素、β-连环蛋白、Sox基因和细胞周期蛋白基因）在CSAV-或CSAV+中的表达均未改变。本研究显示CSAV上存在持续的动脉粥样硬化炎症。此外，未发现成骨细胞分化过程启动的证据。他汀类药物对患者的预处理部分中和了主动脉瓣上的炎症基因模式。这表明他汀类药物对钙化主动脉瓣炎症的早期发展有显著益处。
