Loss of talin in cardiac fibroblasts results in augmented ventricular cardiomyocyte hypertrophy in response to pressure overload.
Loss of talin in cardiac fibroblasts results in augmented ventricular cardiomyocyte hypertrophy in response to pressure overload.
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心脏成纤维细胞中talin的缺失导致压力超负荷时心室心肌细胞肥大加剧。
DOI：
10.1152/ajpheart.00632.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Merryman,WDavid
中科院分区：
文献类型：
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作者：
Noll,NatalieA;Riley,LanceA;Moore,ChristyS;Zhong,Lin;Bersi,MathewR;West,JamesD;Zent,Roy;Merryman,WDavid
心脏的压力超负荷以向心性肥大和间质纤维化为特征。心室壁中的心脏成纤维细胞（CF）在损伤期间变得活化，并合成和压实细胞外基质，这导致心室心脏壁的间质纤维化和硬化。Talin 1（Tln 1）和Talin 2（Tln 2）是机械敏感蛋白，其参与从细胞外环境到CF的肌动蛋白细胞骨架的信号的粘着斑传递。本研究的目的是确定从CF中去除Tln 1和Tln 2是否会减少间质纤维化和心肌肥大。通过渗透泵给予10周龄雄性和雌性Tln 2-null（Tln 2 −/−）和Tln 2-null、CF特异性Tln 1敲除（Tln 2 −/−; Tln 1CF −/−）小鼠血管紧张素II（ANG II）（1.5 mg/kg/天）或生理盐水8周。在ANG II输注的雄性Tln 2 −/−; Tln 1CF −/−小鼠中，心肌细胞面积和心脏厚度测量值增加，而间质纤维化没有增加。与Tln 2 −/−小鼠相比，输注ANG II后，雌性Tln 2 −/−; Tln 1CF −/−小鼠的收缩压升高。然而，在Tln 2 −/−; Tln 1CF −/−小鼠中没有观察到心脏肥大的增加，而在Tln 2 −/−小鼠中观察到心脏肥大的增加。总的来说，这些数据表明，在雄性小鼠中，CF中Tln 1和Tln 2的缺乏导致响应于ANG II的心肌细胞肥大，而在雌性小鼠中导致抗肥大表型。这些研究结果具有重要意义的机械敏感蛋白在CF中的作用，其对心肌细胞功能的影响，在高血压和心肌hypertrophy.NEW的发病机制，值得注意的是，talins的作用以前已经在心肌细胞中进行了研究，但是，这些mechanoconductive蛋白的粘着斑复合物的成员还没有被检查在心脏成纤维细胞以前。我们假设在压力超负荷模型中，心脏成纤维细胞中talins的缺失会减少心脏间质纤维化。然而，我们发现，虽然talins的损失并没有改变纤维化，它确实导致心肌细胞和心室肥大。
Pressure overload of the heart is characterized by concentric hypertrophy and interstitial fibrosis. Cardiac fibroblasts (CFs) in the ventricular wall become activated during injury and synthesize and compact the extracellular matrix, which causes interstitial fibrosis and stiffening of the ventricular heart walls. Talin1 (Tln1) and Talin2 (Tln2) are mechanosensitive proteins that participate in focal adhesion transmission of signals from the extracellular environment to the actin cytoskeleton of CFs. The aim of the present study was to determine whether the removal of Tln1 and Tln2 from CFs would reduce interstitial fibrosis and cardiac hypertrophy. Twelve-week-old male and female Tln2-null (Tln2−/−) and Tln2-null, CF-specific Tln1 knockout (Tln2−/−;Tln1CF−/−) mice were given angiotensin-II (ANG II) (1.5 mg/kg/day) or saline through osmotic pumps for 8 wk. Cardiomyocyte area and measures of heart thickness were increased in the male ANG II-infusedTln2−/−;Tln1CF−/−mice, whereas there was no increase in interstitial fibrosis. Systolic blood pressure was increased in the femaleTln2−/−;Tln1CF−/−mice after ANG II infusion compared with theTln2−/−mice. However, there was no increase in cardiac hypertrophy in theTln2−/−;Tln1CF−/−mice, which was seen in theTln2−/−mice. Collectively, these data indicate that in male mice, the absence of Tln1 and Tln2 in CFs leads to cardiomyocyte hypertrophy in response to ANG II, whereas it results in a hypertrophy-resistant phenotype in female mice. These findings have important implications for the role of mechanosensitive proteins in CFs and their impact on cardiomyocyte function in the pathogenesis of hypertension and cardiac hypertrophy.NEW & NOTEWORTHYThe role of talins has been previously studied in cardiomyocytes; however, these mechanotransductive proteins that are members of the focal adhesion complex have not been examined in cardiac fibroblasts previously. We hypothesized that loss of talins in cardiac fibroblasts would reduce interstitial fibrosis in the heart with a pressure overload model. However, we found that although loss of talins did not alter fibrosis, it did result in cardiomyocyte and ventricular hypertrophy.