Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice
Decreased p110α catalytic activity accompanies increased myocyte apoptosis and cardiac hypertrophy in leptin deficient ob/ob mice
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DOI：
10.4161/cc.7.5.5529
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发表时间：
2008-03-01
期刊：
影响因子：
4.3
通讯作者：
Barouch, Lili A.
中科院分区：
文献类型：
--
作者：
Trivedi, Premal;Yang, Ronghua;Barouch, Lili A.
瘦素信号传导的中断与肥胖和心力衰竭都有关。我们最近发现肥胖症/肥胖症小鼠的瘦素缺乏和肥胖症/肥胖症小鼠的瘦素不敏感性导致心肌细胞凋亡和左心室（LV）肥大增加。我们发现，虽然年轻ob/ob和野生型（WT）小鼠的LV质量相似，但老年ob/ob和db/db小鼠的LV质量显著高于WT。Ob/ob和db/db小鼠心肌细胞凋亡率明显增加，TUNEL和活化的caspase-3水平。肥胖相关的心脏肥大和凋亡的研究的一个有趣的候选人是PI 3 K，其功能不仅是调节细胞大小，而且通过保护细胞免于凋亡来维持细胞的完整性。在这里，我们进一步表明，ob/ob小鼠具有降低的磷酸肌醇3-激酶（PI 3 K）（p110 a）的催化活性，这是逆转与瘦素治疗。肥胖症/肥胖症小鼠中的瘦素补充也将心肌细胞凋亡和LV肥大降低至WT水平。因此，我们得出结论，正常的瘦素信号传导是必要的，以防止年龄相关的心肌细胞凋亡和左心室肥大，PI 3 K是瘦素信号传导轴的关键组成部分。p110 a催化活性的降低可以解释这些肥胖小鼠模型中心肌细胞凋亡增加和心肌肥大的发展。
Disruption of leptin signaling has been associated with both obesity and heart failure. We recently demonstrated that leptin deficiency in ob/ob mice and leptin insensitivity in db/db mice leads to increased myocyte apoptosis and left ventricular (LV) hypertrophy. We showed that LV mass, while similar among young ob/ob, and wild type (WT) mice, is significantly higher in old ob/ob and db/db versus WT. Ob/ob and db/db mice developed markedly increased rates of myocyte apoptosis by TUNEL and activated caspase-3 levels. An intriguing candidate for the study of obesity-associated cardiac hypertrophy and apoptosis is PI3K, which functions to not only regulate cell size but also maintain cell integrity through protection from apoptosis. Here we further show that ob/ob mice have decreased catalytic activity of phosphoinositide 3-kinase (PI3K) (p110a) which is reversed with leptin treatment. Leptin repletion in ob/ob mice also reduced both myocyte apoptosis and LV hypertrophy to WT levels. We have therefore concluded that normal leptin signaling is necessary to prevent age-related myocyte apoptosis and LV hypertrophy and that PI3K is a critical component of the leptin signaling axis. The decrease in p110a catalytic activity could explain the development of increased myocyte apoptosis and cardiac hypertrophy in these obese mouse models.