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研究生:戴豪志
研究生(外文):Hao-Chih Tai
論文名稱:PPARgamma低表達量小鼠脈壓升高機制之研究
論文名稱(外文):Study the Mechanism of Increased Pulse Pressure in PPARgamma Hypomorphic Mice
指導教授:蔡曜聲蔡曜聲引用關係
指導教授(外文):Yau-Sheng Tsai
學位類別:碩士
校院名稱:國立成功大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:66
中文關鍵詞:過氧化體增生受體脈壓動脈硬化彈力蛋白
外文關鍵詞:elastinaortic stiffnessPPARgammapulse pressure
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過氧化體增生受體(Peroxisome proliferator-activated receptor gamma, PPARgamma)為一種核內受體,目前最為人所知的功能為調控脂肪細胞發育及維持葡萄糖之恆定。先前研究已發現,PPARgamma基因功能缺失突變的病患有高血壓的症狀,而給予PPARgamma活化劑的實驗動物和病人則顯示PPARgamma活化劑具降低血壓的效果。究竟PPARgamma如何影響血壓、血管功能與結構,其中機制仍未完全了解。為了研究PPARgamma在高血壓與血管疾病中所扮演之角色,我們利用實驗室已建立之PPARgamma低表達量小鼠(PpargC/-)做為研究工具。初步結果顯示PPARgamma低表達量小鼠收縮壓升高但舒張壓並無明顯的差異,因此造成收縮壓與舒張壓之差─脈壓顯著地上升。目前認為大動脈失去彈性,或大動脈硬化是造成脈壓升高的重要因子之一。因此,本實驗假設PPARgamma缺失將會造成主動脈硬化,進而導致脈壓上升。首先利用臨床上用於判斷動脈硬化的參數,脈搏波傳遞速度(Pulse wave velocity, PWV) 檢驗PpargC/-小鼠是否有動脈硬化的情況。結果顯示PpargC/-小鼠的PWV顯著高於野生型小鼠,表示PpargC/-小鼠可能有動脈硬化現象。進一步分析提供血管彈性的結構蛋白─彈力蛋白(elastin)的表達量後可發現,PpargC/-小鼠主動脈中彈力蛋白的表達量明顯少於野生型小鼠,且PpargC/-小鼠中彈力蛋白的表達量與PWV呈現負相關。此外,matrix metalloproteinase-9 (MMP-9)為一種分解胞外基質(extracellular matrix)的酵素,可分解包括elastin在內的血管結構蛋白,並參與在動脈硬化進程中,MMP-9表達量在PpargC/-小鼠主動脈中也顯著上升。以PPARgamma活化劑rosiglitazone給予PpargC/-小鼠後,原先顯著升高的PWV有減輕的現象,此現象可能與rosiglitazone可減緩MMP-9上升或elastin下降有關。由以上結果可知,PPARgamma缺失可造成主動脈失去彈性,而形成動脈硬化,最終導致脈壓上升。本研究也顯示PPARgamma在血壓調控以及血管活性中的重要性。
Peroxisome proliferator-activated receptor gamma (PPARgamma) is the nuclear receptor that regulates adipocyte development and glucose homeostasis. Loss-of-function mutations in the PPARgamma gene are implicated in human hypertension and PPARgamma agonists decrease blood pressure both in animal models and in human patients. How PPARgamma affects blood pressure and vascular reactivity is still unclear in vivo. To study the role of PPARgamma in the pathogenesis of hypertension and vascular diseases, we generated mice with extremely low PPARgamma level. Our previous data showed that mice with low PPARgamma level exhibited increased systolic blood pressure without significant change in diastolic blood pressure, resulting in a significant increase of pulse pressure. The loss of elasticity of the aorta, generally termed aortic stiffness, is thought to be one of the most important factors in the development of increased pulse pressure. Thus, we hypothesized that PPARgamma deficiency caused aortic stiffness, resulting in the increase in pulse pressure. First, we found that aortic pulse wave velocity (PWV), a non-invasive assessment of aortic stiffness, was significantly increased in PPARgamma hypomorphic mice, suggesting the aortas of PPARgamma hypomorphic mice were stiffer than wild-type mice. The expression of elastin, a prominent structural protein contributing to aortic distensibility, was significantly decreased in aortas of PPARgamma hypomorphic mice. Furthermore, the elastin expression was negatively correlated with aortic PWV in PPARgamma hypomorphic mice. In addition, the expression of matrix metalloproteinase-9 (MMP-9), which is reported to be able to break down elastin and involved in the process of arterial stiffening, was significantly increased in aortas of PPARgamma hypomorphic mice. The elevated PWV in PpargC/- mice was ameliorated after treatment of PPARgamma agonist, which was associated with attenuated expressions of decreased elastin and increased MMP-9. Together, our results suggest that PPARgamma deficiency causes loss of elasticity in aorta and development of aortic stiffness, further resulting in elevated pulse pressure. This study underscores the importance of PPARgamma in the regulation of blood pressure and vascular reactivity.
INTRODUCTION ............................................................................................................... 1
Peroxisome proliferator-activated receptor γ ................................................................. 1
PPARγ and blood pressure ............................................................................................. 2
PPARγ deficiency and hypertension .............................................................................. 3
High pulse pressure ....................................................................................................... 4
Arterial stiffness ............................................................................................................ 5
Ectopic fat and vascular disease .................................................................................... 8
The effects of PPARγ agonists in vascular diseases ...................................................... 9
Significance ................................................................................................................. 10
MATERIALS AND METHODS ...................................................................................... 11
Animals ........................................................................................................................ 11
Blood pressure measurements ..................................................................................... 11
Assessment of cardiac function by echocardiography ................................................ 12
Measurement of pulse wave velocity .......................................................................... 12
Storage of tissue samples ............................................................................................. 13
Tissue RNA extraction ................................................................................................. 13
Reverse transcription and real-time polymerase chain reaction (real-time PCR) ....... 14
Western blotting ........................................................................................................... 15
Histology and elastic fiber stain .................................................................................. 16
Rosiglitazone treatment ............................................................................................... 17
Data analysis ................................................................................................................ 17
RESULTS ........................................................................................................................... 18
Quantitative effects of PPARγ on blood pressure ........................................................ 18
Increased pulse pressure in PpargC/- mice ................................................................... 18
Determine the possible causes of high pulse pressure in PpargC/- mice ..................... 19
Elevated aortic pulse wave velocity in PpargC/- mice ................................................. 20
Elastin expression was downregulated in PpargC/- mice ............................................. 20
Histological analysis of elastin fiber content, fragmentation, and wall structure ....... 22
Increase in inflammation in aortas of PpargC/- mice ................................................... 23
Ectopic perivascular fat deposition in PpargC/- mice .................................................. 24
Other possible mechanism involved in vascular function and blood pressure
regulation ..................................................................................................................... 25
Elevated aortic pulse wave velocity was ameliorated in PpargC/- mice after treatment
of PPARγ agonist ......................................................................................................... 26
DISCUSSION ..................................................................................................................... 27
REFERENCES .................................................................................................................. 35
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