Metoprolol and bisoprolol ameliorate hypertrophy of neonatal rat cardiomyocytes induced by high glucose via the PKC/NF-κB/c-fos signaling pathway
Metoprolol and bisoprolol ameliorate hypertrophy of neonatal rat cardiomyocytes induced by high glucose via the PKC/NF-κB/c-fos signaling pathway
复制标题
美托洛尔和比索洛尔通过 PKC/NF-κB/c-fos 信号通路改善高糖诱导的新生大鼠心肌细胞肥大
DOI：
10.3892/etm.2019.8312
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发表时间：
2020-02-01
影响因子：
2.7
通讯作者：
Zhang, Wenbin
中科院分区：
文献类型：
--
作者：
Wang, Min;Lv, Qingbo;Zhang, Wenbin
糖尿病引起的高血糖会增加糖尿病心肌病的风险。然而，据我们所知，这一过程的潜在机制仍然没有得到充分的探索。因此，开发预防高血糖的方法对糖尿病患者可能是有益的。本研究旨在探讨美托洛尔和比索洛尔对乳鼠心肌细胞肥大的影响。心肌细胞在两种类型的培养液中培养：一种是低葡萄糖水平，另一种是高葡萄糖水平。高糖培养的心肌细胞进一步用蛋白激酶C抑制剂、核因子κB抑制剂、美托洛尔或比索洛尔处理。测定心肌细胞搏动频率、细胞直径和表面积。用逆转录-定量聚合酶链式反应检测心钠素、α-肌球蛋白重链(α-MHc)和β-肌球蛋白重链(β-MHc)基因表达水平；用免疫印迹法检测PKC-α、PKC-β2、NF-κB、肿瘤坏死因子-α(α-α)和c-fos的表达和活化。美托洛尔或比索洛尔与蛋白激酶C抑制剂或核因子-κB抑制剂联合使用，以确定肥厚反应是否会比单独使用美托洛尔或比索洛尔更低程度地减弱。高糖培养的心肌细胞搏动频率、细胞直径、表面积、蛋白质含量和合成增加，心钠素和β-MHC表达增加，α-MHC表达降低。高糖还可上调PKC-α、PKC-β2、NF-κB、α和c-fos的表达和活化。美托洛尔和比索洛尔可部分逆转上述变化，而美托洛尔或比索洛尔与PKC抑制剂或NF-κB抑制剂联用可进一步改善上述肥大反应，使其降至低于单用美托洛尔或比索洛尔水平。结论：美托洛尔和比索洛尔可通过抑制总的和磷酸化的PKC-α，进而影响PKC-α/NF-κB/c-fos信号通路，从而抑制高糖培养的心肌细胞肥大。
Hyperglycemia caused by diabetes mellitus could increase the risk of diabetic cardiomyopathy. However, to the best of our knowledge, the underlying mechanism of this process is still not fully explored. Thus, developing ways to prevent hyperglycemia can be beneficial for diabetic patients. The present study was designed to investigate the influence of metoprolol and bisoprolol on the cardiomyocytic hypertrophy of neonatal rat cardiomyocytes. Cardiomyocytes were cultured in two types of media: One with low glucose levels and one with high glucose levels. Cardiomyocytes cultured in high glucose were further treated with the following: A protein kinase C (PKC) inhibitor, an NF-κB inhibitor, metoprolol or bisoprolol. The pulsatile frequency, cellular diameter and surface area of cardiomyocytes were measured. Protein content and [3H]-leucine incorporation were determined, atrial natriuretic peptide (ANP), α-myosin heavy chain (α-MHC) and β-myosin heavy chain (β-MHC) mRNA levels were calculated by reverse transcription-quantitative PCR, while the expression and activation of PKC-α, PKC-β2, NF-κB, tumor necrosis factor-α (TNF-α), and c-fos were detected by western blotting. Metoprolol or bisoprolol were also used in combination with PKC inhibitor or NF-κB inhibitor to determine whether the hypertrophic response would be attenuated to a lower extent compared with metroprolol or bisoprolol alone. Cardiomyocytes cultured in high glucose presented increased pulsatile frequency, cellular diameter, surface area, and protein content and synthesis, higher expression of ANP and β-MHC, and lower α-MHC expression. High glucose levels also upregulated the expression and activation of PKC-α, PKC-β2, NF-κB, TNF-α and c-fos. Metoprolol and bisoprolol partly reversed the above changes, while combined use of metoprolol or bisoprolol with PKC inhibitor or NF-κB inhibitor further ameliorated the hypertrophic response mentioned above to lower levels compared with using metroprolol or bisoprolol alone. In conclusion, metoprolol and bisoprolol could prevent hypertrophy of cardiomyocytes cultured in high glucose by the inhibition of the total and phospho-PKC-α, which could further influence the PKC-α/NF-κB/c-fos signaling pathway.