Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.
Targeted inhibition of calpain reduces myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes.
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作者：
Li Y;Ma J;Zhu H;Singh M;Hill D;Greer PA;Arnold JM;Abel ED;Peng T
最近，我们发现钙蛋白酶-1的激活有助于高血糖诱导的心肌细胞凋亡。本研究旨在研究钙蛋白酶的靶向干扰是否会减少1型糖尿病小鼠模型的心肌肥厚和纤维化。通过注射链脲佐菌素（STZ）诱导小鼠糖尿病，OVE 26小鼠也被用作1型糖尿病模型。钙蛋白酶的功能通过小鼠心肌细胞特异性敲除Capn 4和使用钙蛋白酶抑制剂转基因小鼠进行遗传操纵。在STZ注射后2个月和5个月或在5个月龄的OVE 26糖尿病小鼠中研究心肌肥大和纤维化。培养分离的成年小鼠心脏成纤维细胞也在高糖条件下进行了研究。钙蛋白酶活性，心肌细胞横截面积，心肌胶原沉积显着增加STZ诱导和OVE 26糖尿病心脏，这些都伴随着肥厚和纤维化胶原基因的表达升高。Capn 4的缺乏或钙蛋白酶抑制蛋白的过表达减少了两种糖尿病模型中的心肌肥厚和纤维化，导致心肌功能的改善。这些作用与糖尿病心脏中活化的T细胞核因子-κB和基质金属蛋白酶（MMP）活性的核因子正常化有关。在培养的心脏成纤维细胞中，高葡萄糖诱导的增殖和MMP活性被钙蛋白酶抑制剂阻止。糖尿病小鼠心肌肥厚和纤维化可通过钙蛋白酶功能降低而减轻。因此，靶向抑制钙蛋白酶代表了逆转糖尿病心肌病的潜在新治疗策略。
Recently we have shown that calpain-1 activation contributes to cardiomyocyte apoptosis induced by hyperglycemia. This study was undertaken to investigate whether targeted disruption of calpain would reduce myocardial hypertrophy and fibrosis in mouse models of type 1 diabetes. Diabetes in mice was induced by injection of streptozotocin (STZ), and OVE26 mice were also used as a type 1 diabetic model. The function of calpain was genetically manipulated by cardiomyocyte-specific knockout Capn4 in mice and the use of calpastatin transgenic mice. Myocardial hypertrophy and fibrosis were investigated 2 and 5 months after STZ injection or in OVE26 diabetic mice at the age of 5 months. Cultured isolated adult mouse cardiac fibroblast cells were also investigated under high glucose conditions. Calpain activity, cardiomyocyte cross-sectional areas, and myocardial collagen deposition were significantly increased in both STZ-induced and OVE26 diabetic hearts, and these were accompanied by elevated expression of hypertrophic and fibrotic collagen genes. Deficiency of Capn4 or overexpression of calpastatin reduced myocardial hypertrophy and fibrosis in both diabetic models, leading to the improvement of myocardial function. These effects were associated with a normalization of the nuclear factor of activated T-cell nuclear factor-κB and matrix metalloproteinase (MMP) activities in diabetic hearts. In cultured cardiac fibroblasts, high glucose–induced proliferation and MMP activities were prevented by calpain inhibition. Myocardial hypertrophy and fibrosis in diabetic mice are attenuated by reduction of calpain function. Thus targeted inhibition of calpain represents a potential novel therapeutic strategy for reversing diabetic cardiomyopathy.
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影响因子：
7.7
作者：
Li J;Zhu H;Shen E;Wan L;Arnold JM;Peng T
通讯作者：
Peng T
DOI：
10.1152/ajpheart.00583.2005
发表时间：
2006-01-01
影响因子：
4.8
作者：
Greer, JJM;Ware, DP;Lefer, DJ
通讯作者：
Lefer, DJ
影响因子：
5.3
作者：
Arthur, JSC;Elce, JS;Greer, PA
通讯作者：
Greer, PA
DOI：
10.1152/ajpheart.00124.2004
发表时间：
2004-10-01
影响因子：
4.8
作者：
Li, YH;Ha, TZ;Li, CF
通讯作者：
Li, CF
影响因子：
64.8
作者：
Hanna, Rachel A.;Campbell, Robert L.;Davies, Peter L.
通讯作者：
Davies, Peter L.