Telomere dynamics during aging in polygenic left ventricular hypertrophy
Telomere dynamics during aging in polygenic left ventricular hypertrophy
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DOI：
10.1152/physiolgenomics.00083.2015
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发表时间：
2016-01-01
影响因子：
4.6
通讯作者：
Charchar, Fadi J.
中科院分区：
文献类型：
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作者：
Marques, Francine Z.;Booth, Scott A.;Charchar, Fadi J.
短端粒与心血管疾病风险增加有关。在这里，我们研究了心肌细胞端粒长度在心肌肥厚和心脏衰竭的个体发育过程中的关键年龄在肥厚的心脏大鼠（HHR），并与正常的心脏大鼠（NHR）的控制株。关键年龄与病理生理学顺序相对应，开始时心肌细胞较少（2天），导致左心室肥大（LVH）（13周），随后进展为心力衰竭（38周）。我们测量了端粒长度，端粒酶组织活性，端粒酶逆转录酶（Tert）和端粒酶RNA组分（Terc）的mRNA水平，以及端粒调节因子microRNA miR-34 a的表达。心脏端粒长度在2天和38周时HHR比对照株长，但在13周时短。新生儿HHR心肌端粒酶活性及Tert和miR-34 a表达均高于正常对照组。13周和38周时端粒酶活性无差异。Tert mRNA和Terc RNA在38 wk时过表达，而miR-34 a在13 wk时过表达，但在38 wk时下调。循环白细胞与心脏端粒长度仅在HHR中密切相关。HHR中较长的新生儿端粒可能反映了胎儿和出生后早期心肌细胞分裂较少，并解释了易于后期肥大和衰竭的总心肌细胞补体减少。尽管较短的端粒是13周时心脏肥大的一个特征，但在38周时进展为心力衰竭时并不存在。
Short telomeres are associated with increased risk of cardiovascular disease. Here we studied cardiomyocyte telomere length at key ages during the ontogeny of cardiac hypertrophy and failure in the hypertrophic heart rat (HHR) and compared these with the normal heart rat (NHR) control strain. Key ages corresponded with the pathophysiological sequence beginning with fewer cardiomyocytes (2 days), leading to left ventricular hypertrophy (LVH) (13 wk) and subsequently progression to heart failure (38 wk). We measured telomere length, tissue activity of telomerase, mRNA levels of telomerase reverse transcriptase (Tert) and telomerase RNA component (Terc), and expression of the telomeric regulator microRNA miR-34a. Cardiac telomere length was longer in the HHR compared with the control strain at 2 days and 38 wk, but shorter at 13 wk. Neonatal HHR had higher cardiac telomerase activity and expression of Tert and miR-34a. Telomerase activity was not different at 13 or 38 wk. Tert mRNA and Terc RNA were overexpressed at 38 wk, while miR-34a was overexpressed at 13 wk but downregulated at 38 wk. Circulating leukocytes were strongly correlated with cardiac telomere length in the HHR only. The longer neonatal telomeres in HHR are likely to reflect fewer fetal and early postnatal cardiomyocyte cell divisions and explain the reduced total cardiomyocyte complement that predisposes to later hypertrophy and failure. Although shorter telomeres were a feature of cardiac hypertrophy at 13 wk, they were not present at the progression to heart failure at 38 wk.