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Selective inhibition of PKCβ2 improves Caveolin-3/eNOS signaling and attenuates lipopolysaccharide-induced injury by inhibiting autophagy in H9C2 cardiomyocytes
Journal of Molecular Histology ( IF 2.9 ) Pub Date : 2021-06-08 , DOI: 10.1007/s10735-021-09990-0
Zhou Yang 1 , Wating Su 1 , Yuan Zhang 1 , Lu Zhou 1 , Zhong-Yuan Xia 1 , Shaoqing Lei 1
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Lipopolysaccharide (LPS)-induced autophagy is involved in sepsis-associated myocardial injury with increased PKCβ2 activation. We previously found hyperglycemia-induced PKCβ2 activation impaired the expression of caveolin-3 (Cav-3), the dominant isoform to form cardiomyocytes caveolae which modulate eNOS signaling to confer cardioprotection in diabetes. However, little is known about the roles of PKCβ2 in autophagy and Cav-3/eNOS signaling in cardiomyocytes during LPS exposure. We hypothesize LPS-induced PKCβ2 activation promotes autophagy and impairs Cav-3/eNOS signaling in LPS-treated cardiomyocytes. H9C2 cardiomyocytes were treated with LPS (10 µg/mL) in the presence or absence of PKCβ2 inhibitor CGP53353 (CGP, 1 µM) or autophagy inhibitor 3-methyladenine (3-MA, 10 µM). LPS stimulation induced cytotoxicity overtime in H9C2 cardiomyocytes, accompanied with excessive PKCβ2 activation. Selective inhibition of PKCβ2 with CGP significantly reduced LPS-induced cytotoxicity and autophagy (measured by LC-3II, Beclin-1, p62 and autophagic flux). In addition, CGP significantly attenuated LPS-induced oxidative injury, and improved Cav-3 expression and eNOS activation, similar effects were shown by the treatment of autophagy inhibitor 3-MA. LPS-induced myocardial injury is associated with excessive PKCβ2 activation, which contributes to elevated autophagy and impaired Cav-3/eNOS signaling. Selective inhibition of PKCβ2 improves Cav-3/eNOS signaling and attenuates LPS-induced injury through inhibiting autophagy in H9C2 cardiomyocytes.



中文翻译:

选择性抑制 PKCβ2 通过抑制 H9C2 心肌细胞的自噬改善 Caveolin-3/eNOS 信号传导并减轻脂多糖诱导的损伤

脂多糖 (LPS) 诱导的自噬与脓毒症相关的心肌损伤有关,PKCβ2 活化增加。我们之前发现高血糖诱导的 PKCβ2 激活损害了小窝蛋白 3 (Cav-3) 的表达,Cav-3 是形成心肌细胞小窝的主要同种型,可调节 eNOS 信号传导以赋予糖尿病心脏保护作用。然而,关于 PKCβ2 在 LPS 暴露期间心肌细胞自噬和 Cav-3/eNOS 信号传导中的作用知之甚少。我们假设 LPS 诱导的 PKCβ2 激活促进自噬并损害 LPS 处理的心肌细胞中的 Cav-3/eNOS 信号传导。在存在或不存在 PKCβ2 抑制剂 CGP53353 (CGP, 1 µM) 或自噬抑制剂 3-甲基腺嘌呤 (3-MA, 10 µM) 的情况下,用 LPS (10 µg/mL) 处理 H9C2 心肌细胞。LPS 刺激在 H9C2 心肌细胞中诱导细胞毒性超时,伴随着过度的PKCβ2激活。用 CGP 选择性抑制 PKCβ2 显着降低 LPS 诱导的细胞毒性和自噬(通过 LC-3II、Beclin-1、p62 和自噬通量测量)。此外,CGP 显着减轻 LPS 诱导的氧化损伤,并改善 Cav-3 表达和 eNOS 活化,自噬抑制剂 3-MA 的治疗也显示出类似的效果。LPS 诱导的心肌损伤与过度的 PKCβ2 激活有关,这导致自噬升高和 Cav-3/eNOS 信号传导受损。PKCβ2 的选择性抑制可改善 Cav-3/eNOS 信号传导并通过抑制 H9C2 心肌细胞中的自噬来减轻 LPS 诱导的损伤。Beclin-1、p62 和自噬通量)。此外,CGP 显着减轻 LPS 诱导的氧化损伤,并改善 Cav-3 表达和 eNOS 活化,自噬抑制剂 3-MA 的治疗也显示出类似的效果。LPS 诱导的心肌损伤与过度的 PKCβ2 激活有关,这导致自噬升高和 Cav-3/eNOS 信号传导受损。PKCβ2 的选择性抑制可改善 Cav-3/eNOS 信号传导并通过抑制 H9C2 心肌细胞中的自噬来减轻 LPS 诱导的损伤。Beclin-1、p62 和自噬通量)。此外,CGP 显着减轻 LPS 诱导的氧化损伤,并改善 Cav-3 表达和 eNOS 活化,自噬抑制剂 3-MA 的治疗也显示出类似的效果。LPS 诱导的心肌损伤与过度的 PKCβ2 激活有关,这导致自噬升高和 Cav-3/eNOS 信号传导受损。PKCβ2 的选择性抑制可改善 Cav-3/eNOS 信号传导并通过抑制 H9C2 心肌细胞中的自噬来减轻 LPS 诱导的损伤。这导致自噬升高和 Cav-3/eNOS 信号传导受损。PKCβ2 的选择性抑制可改善 Cav-3/eNOS 信号传导并通过抑制 H9C2 心肌细胞中的自噬来减轻 LPS 诱导的损伤。这导致自噬升高和 Cav-3/eNOS 信号传导受损。PKCβ2 的选择性抑制可改善 Cav-3/eNOS 信号传导并通过抑制 H9C2 心肌细胞中的自噬来减轻 LPS 诱导的损伤。

更新日期:2021-06-09
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