Supplemental Digital Content is available in the text. Systemic hypertension increases cardiac workload causing cardiomyocyte hypertrophy and increased cardiac fibrosis. An underlying feature is increased production of reactive oxygen species. Redox-sensitive ASK1 (apoptosis signal-regulating kinase 1) activates stress-regulated protein kinases (p38-MAPK [mitogen-activated protein kinases] and JNKs [c-Jun N-terminal kinases]) and promotes fibrosis in various tissues. Here, we determined the specificity of ASK1 signaling in the heart, with the hypothesis that ASK1 inhibitors may be used to manage fibrosis in hypertensive heart disease. Using immunoblotting, we established that moderate levels of H2O2 activate ASK1 in neonatal rat cardiomyocytes and perfused rat hearts. ASK1 was activated during ischemia in adult rat hearts, but not on reperfusion, consistent with activation by moderate (not high) reactive oxygen species levels. In contrast, IL (interleukin)-1β activated an alternative kinase, TAK1 (transforming growth factor–activated kinase 1). ASK1 was not activated by IL1β in cardiomyocytes and activation in perfused hearts was due to increased reactive oxygen species. Selonsertib (ASK1 inhibitor) prevented activation of p38-MAPKs (but not JNKs) by oxidative stresses in cultured cardiomyocytes and perfused hearts. In vivo (C57Bl/6J mice with osmotic minipumps for drug delivery), selonsertib (4 mg/[kg·d]) alone did not affect cardiac function/dimensions (assessed by echocardiography). However, it suppressed hypertension-induced cardiac hypertrophy resulting from angiotensin II (0.8 mg/[kg·d], 7d), with inhibition of Nppa/Nppb mRNA upregulation, reduced cardiomyocyte hypertrophy and, notably, significant reductions in interstitial and perivascular fibrosis. Our data identify a specific reactive oxygen species→ASK1→p38-MAPK pathway in the heart and establish that ASK1 inhibitors protect the heart from hypertension-induced cardiac remodeling. Thus, targeting the ASK1→p38-MAPK nexus has potential therapeutic viability as a treatment for hypertensive heart disease.

中文翻译：

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心脏 ASK1（细胞凋亡信号调节激酶 1）的氧化还原调节控制 p38-MAPK（丝裂原激活蛋白激酶）并协调心脏重塑至高血压

补充数字内容在文本中可用。全身性高血压会增加心脏负荷，导致心肌细胞肥大和心脏纤维化增加。一个潜在的特征是活性氧的产生增加。氧化还原敏感性 ASK1（细胞凋亡信号调节激酶 1）激活应激调节蛋白激酶（p38-MAPK [丝裂原活化蛋白激酶] 和 JNKs [c-Jun N-末端激酶]）并促进各种组织的纤维化。在这里，我们确定了 ASK1 信号在心脏中的特异性，假设 ASK1 抑制剂可用于控制高血压心脏病的纤维化。使用免疫印迹，我们确定中等水平的 H2O2 激活新生大鼠心肌细胞和灌注大鼠心脏中的 ASK1。ASK1 在成年大鼠心脏缺血期间被激活，但在再灌注时未激活，与中等（不高）活性氧水平的活化一致。相比之下，IL（白细胞介素）-1β 激活了替代激酶 TAK1（转化生长因子激活激酶 1）。ASK1 在心肌细胞中不被 IL1β 激活，灌注心脏中的激活是由于活性氧增加。Selonsertib（ASK1 抑制剂）通过培养的心肌细胞和灌注心脏中的氧化应激阻止 p38-MAPK（但不是 JNK）的激活。在体内（C57Bl/6J 小鼠具有用于药物递送的渗透性微型泵），单独使用 selonsertib (4 mg/[kg·d]) 不影响心脏功能/尺寸（通过超声心动图评估）。然而，它抑制由血管紧张素 II (0.8 mg/[kg·d], 7d) 引起的高血压诱导的心脏肥大，抑制 Nppa/Nppb mRNA 上调，减少心肌细胞肥大，值得注意的是，间质和血管周围纤维化显着减少。我们的数据确定了心脏中特定的活性氧类→ASK1→p38-MAPK 通路，并确定 ASK1 抑制剂保护心脏免受高血压引起的心脏重塑。因此，靶向 ASK1→p38-MAPK 关系作为高血压心脏病的治疗具有潜在的治疗可行性。