Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension
Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension
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DOI：
10.1161/hypertensionaha.119.14556
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发表时间：
2020-10-01
期刊：
影响因子：
8.3
通讯作者：
Clerk, Angela
中科院分区：
文献类型：
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作者：
Meijles, Daniel N.;Cull, Joshua J.;Clerk, Angela
全身性高血压增加心脏工作负荷，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ASK 1（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JNK [c-Jun N-末端激酶]），并促进各种组织中的纤维化。在这里，我们确定了心脏中ASK 1信号传导的特异性，假设ASK 1抑制剂可用于管理高血压心脏病中的纤维化。使用免疫印迹法，我们确定了中等水平的H（2）O（2）激活新生大鼠心肌细胞和灌流大鼠心脏中的ASK 1。ASK 1在成年大鼠心脏缺血过程中被激活，但在再灌注过程中没有被激活，这与中等（不高）活性氧水平的激活一致。相反，IL（白细胞介素）-1 β激活了一种替代激酶，TAK 1（转化生长因子激活激酶1）。在心肌细胞中，ASK 1不被IL 1 β激活，而在灌注心脏中的激活是由于活性氧的增加。Selonsertib（ASK 1抑制剂）可防止培养的心肌细胞和灌注心脏中氧化应激引起的p38-MAPK（而非JNK）活化。在体内（C57 Bl/6 J小鼠，使用渗透微型泵进行药物递送），selonsertib（4 mg/[kg中心点d]）单独给药不会影响心脏功能/尺寸（通过超声心动图评估）。然而，它抑制由血管紧张素II引起的高血压诱导的心脏肥大（0.8 mg/[kg center dot d]，7 d），抑制Nppa/NppbmRNA上调，减少心肌细胞肥大，尤其是间质和血管周围纤维化显著减少。我们的数据确定了心脏中特定的活性氧-> ASK 1-> p38-MAPK途径，并确定ASK 1抑制剂可以保护心脏免受高血压诱导的心脏重塑。因此，靶向ASK 1-> p38-MAPK关系作为高血压性心脏病的治疗具有潜在的治疗可行性。
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 H(2)O(2)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)-1 beta activated an alternative kinase, TAK1 (transforming growth factor-activated kinase 1). ASK1 was not activated by IL1 beta 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 center dot 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 center dot d], 7d), with inhibition ofNppa/NppbmRNA 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.