Doxazosin Stimulates Galectin-3 Expression and Collagen Synthesis in HL-1 Cardiomyocytes Independent of Protein Kinase C Pathway.
Doxazosin Stimulates Galectin-3 Expression and Collagen Synthesis in HL-1 Cardiomyocytes Independent of Protein Kinase C Pathway.
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多沙唑嗪刺激 HL-1 心肌细胞中半乳糖凝集素 3 的表达和胶原蛋白的合成，与蛋白激酶 C 通路无关
DOI：
10.3389/fphar.2016.00495
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发表时间：
2016
影响因子：
5.6
通讯作者：
Song X
中科院分区：
文献类型：
--
作者：
Qian X;Li M;Wagner MB;Chen G;Song X
多沙唑嗪是一种常用于治疗高血压和前列腺癌的药物，它会增加心力衰竭的风险。然而，潜在的机制仍不清楚。Galectin-3是一种重要的介质，在心肌肥厚和心力衰竭中起致病作用。在本研究中，我们研究了多沙唑嗪是否能刺激培养的HL-1心肌细胞Galectin-3的表达和胶原的合成。我们发现，多沙唑嗪可剂量依赖性地诱导半乳糖凝集素-3蛋白的表达，当剂量低至0.01μ时，半乳糖凝集素-3蛋白的表达显著增加。多沙唑嗪可上调HL-1心肌细胞I型胶原和α-SMA的蛋白表达，并诱导凋亡蛋白α-3的表达。尽管我们先前报道了蛋白激酶C(PKC)的激活可以刺激Galectin-3的表达，但用PKC抑制剂白屈菜红碱阻断PKC通路并不能阻止多沙唑嗪诱导的Galectin-3和胶原的表达。一直以来，多沙唑嗪治疗不会改变总蛋白激酶C和磷酸化蛋白激酶C。这些结果表明，多沙唑嗪刺激的Galectin-3不依赖于PKC通路。为了确定是否涉及α1-肾上腺素能途径，我们用不可逆的α-肾上腺素能受体阻断剂苯氧苯甲胺预处理细胞，发现多沙唑嗪刺激的Galectin-3和胶原的表达与对照组相似，提示多沙唑嗪的作用独立于α1-肾上腺素能受体阻断。总而言之，我们展示了多沙唑嗪通过刺激心脏纤维化因子Galectin-3表达而对心肌细胞产生的新作用。多沙唑嗪的作用机制既不是通过激活蛋白激酶C途径，也不是通过拮抗α1-肾上腺素能受体。
Doxazosin, a drug commonly prescribed for hypertension and prostate disease, increases heart failure risk. However, the underlying mechanism remains unclear. Galectin-3 is an important mediator that plays a pathogenic role in cardiac hypertrophy and heart failure. In the present study, we investigated whether doxazosin could stimulate galectin-3 expression and collagen synthesis in cultured HL-1 cardiomyocytes. We found that doxazosin dose-dependently induced galectin-3 protein expression, with a statistically significant increase in expression with a dose as low as 0.01 μM. Doxazosin upregulated collagen I and α-smooth muscle actin (α-SMA) protein levels and also induced apoptotic protein caspase-3 in HL-1 cardiomyocytes. Although we previously reported that activation of protein kinase C (PKC) stimulates galectin-3 expression, blocking the PKC pathway with the PKC inhibitor chelerythrine did not prevent doxazosin-induced galectin-3 and collagen expression. Consistently, doxazosin treatment did not alter total and phosphorylated PKC. These results suggest that doxazosin-stimulated galectin-3 is independent of PKC pathway. To determine if the α1-adrenergic pathway is involved, we pretreated the cells with the irreversible α-adrenergic receptor blocker phenoxybenzamine and found that doxazosin-stimulated galectin-3 and collagen expression was similar to controls, suggesting that doxazosin acts independently of α1-adrenergic receptor blockade. Collectively, we show a novel effect of doxazosin on cardiomycytes by stimulating heart fibrosis factor galectin-3 expression. The mechanism of action of doxazosin is not mediated through either activation of the PKC pathway or antagonism of α1-adrenergic receptors.
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影响因子：
5
作者：
Liu Q;Molkentin JD
通讯作者：
Molkentin JD
影响因子：
4.3
作者：
Bayer, AL;Heidkamp, MC;Samarel, AM
通讯作者：
Samarel, AM
影响因子：
82.9
作者：
Braz, JC;Gregory, K;Molkentin, JD
通讯作者：
Molkentin, JD
DOI：
10.1111/j.1365-2125.1986.tb02854.x
发表时间：
1986-01-01
影响因子：
3.4
作者：
FRICK, MH;HALTTUNEN, P;SARASTE, M
通讯作者：
SARASTE, M
影响因子：
1.8
作者：
Ceral, Jiri;Solar, Miroslav
通讯作者：
Solar, Miroslav