Properties of Polyploid Cells in a Model of Aging

衰老模型中多倍体细胞的特性

• 批准号: 6683918
• 负责人: KATYA RAVID
• 金额: $ 8.08万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6683918
• 关键词: age difference; aging; animal old age; aorta; apoptosis; biological models; calcium flux; cell growth regulation; cell population study; cell proliferation; flow cytometry; hypertension; laboratory rat; mature animal; mitogens; muscle cells; muscle contraction; oncoprotein p21; organ culture; polyploidy; protein localization; receptor expression; terminal nick end labeling; tissue /cell culture; vascular smooth muscle

Decreased blood vessel contractility and increased blood pressure occur with aging. The aorticI thickening associated with atherosclerosis, inflammation, hypertension, and aging is primarily duel to vascular smooth muscle cell (VSMC) hypertrophy. This, in turn, results from an increase in DNA content of VSMC, yielding polyploid cells. We found a remarkably robust hyperbolic relation between rat age and the ratio of tetraploid to diploid aortic VSMC. Approximately 60% of VSMC from 36 month old rats are tetraploid, while 25% of VSMC from 24 month old rats and only 8% from 3 month old rats are tetraploid. We hypothesize that these tetraploid VSMC are functionally distinct from diploid cells. We have developed a method for separating diploid aortic VSMC from cells with higher ploidy. In preliminary studies, we found that expression of the cell cycle regulator, p21 is elevated in higher ploidy cells, as occurs in other cell types with aging, implying that ploidy likely impacts the proliferative potential of VSMC. We found that expression of receptors known to modulate calcium mobilization is reduced in tetraploid aortic VSMC isolated from old animals. We will test the functional relevance of the large increase in tetrapoid cells that occurs with aging in the following Specific Aims. Aim 1 is to test the cell dynamic impact of accumulation of tetraploid cells by determining the proliferative potential and apoptotic rates of aortic diploid and tetraploid VSMC derived from old rats. This is relevant to events that are responsible for VSMC accumulation. Aim 2 is to determine differences in calcium mobilization between diploid and tetraploid aortic VSMC derived from old rats. This is important since calcium flux, a key determinant of smooth muscle contractility, is important in the genesis of hypertension, a common condition in the elderly. These Aims will test the impact and relevance of the large increase in VSMC tetraploidy with aging and will point to relevant directions to be pursued in further mechanistic studies.

随着年龄的增长，血管收缩能力下降，血压升高。与动脉粥样硬化、炎症、高血压和衰老相关的主动脉增厚主要与血管平滑肌细胞（VSMC）肥大有关。这反过来又导致VSMC DNA含量的增加，从而产生多倍体细胞。我们发现大鼠年龄与四倍体与二倍体主动脉VSMC的比例之间存在显著的双曲线关系。36月龄大鼠的VSMC约60%为四倍体，而24月龄大鼠的VSMC为25%，3月龄大鼠的VSMC仅为8%。我们假设这些四倍体VSMC在功能上不同于二倍体细胞。我们建立了一种从高倍性细胞中分离二倍体主动脉VSMC的方法。在初步研究中，我们发现细胞周期调节因子p21的表达在高倍性细胞中升高，与其他细胞类型随着年龄的增长一样，这表明倍性可能影响VSMC的增殖潜能。我们发现，在老年动物分离的四倍体主动脉VSMC中，已知调节钙动员的受体表达减少。我们将在以下特定目标中测试随着衰老而发生的四类细胞大量增加的功能相关性。目的1通过测定老年大鼠主动脉二倍体和四倍体VSMC的增殖潜能和凋亡率，探讨四倍体细胞积累对细胞动力学的影响。这与导致VSMC积累的事件有关。目的2是确定二倍体和四倍体老年大鼠主动脉VSMC钙动员的差异。这是很重要的，因为钙通量是平滑肌收缩性的关键决定因素，在高血压的发生中很重要，高血压是老年人的一种常见疾病。这些目的将测试VSMC四倍体大量增加与衰老的影响和相关性，并将为进一步的机制研究指明相关的方向。

项目成果

Increased polyploidy in aortic vascular smooth muscle cells during aging is marked by cellular senescence.

衰老过程中主动脉血管平滑肌细胞多倍体的增加以细胞衰老为标志。

• DOI: 10.1111/j.1474-9726.2007.00274.x
• 发表时间: 2007
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Yang,Dan;McCrann,DonaldJ;Nguyen,Hao;StHilaire,Cynthia;DePinho,RonaldA;Jones,MatthewR;Ravid,Katya
• 通讯作者: Ravid,Katya

Vascular smooth muscle cell polyploidization involves changes in chromosome passenger proteins and an endomitotic cell cycle.

血管平滑肌细胞多倍化涉及染色体乘客蛋白和有丝分裂细胞周期的变化。

• DOI: 10.1016/j.yexcr.2004.12.028
• 发表时间: 2005
• 期刊: Experimental cell research
• 影响因子: 3.7
• 作者: Nagata,Yuka;Jones,MatthewR;Nguyen,HaoG;McCrann,DonaldJ;StHilaire,Cynthia;Schreiber,BarbaraM;Hashimoto,Atsushi;Inagaki,Masaki;Earnshaw,WilliamC;Todokoro,Kazuo;Ravid,Katya
• 通讯作者: Ravid,Katya