Pleiotropic, non-cell death-associated effects of inhibitors of receptor-interacting protein kinase 1 in the heart
Pleiotropic, non-cell death-associated effects of inhibitors of receptor-interacting protein kinase 1 in the heart
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DOI：
10.1007/s11010-021-04136-y
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发表时间：
2021-04-03
影响因子：
4.3
通讯作者：
Adameova，A.
中科院分区：
文献类型：
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作者：
Horvath，C.;Szobi，A.;Adameova，A.
抑制受体相互作用蛋白激酶1（RIP 1）已被公认为限制坏死性凋亡的一个令人信服的工具。最近的研究结果表明，RIP 1抑制剂，necrostatin-1（Nec-1），也能够在非细胞死亡条件下改变心脏功能。在这项研究中，我们研究了其潜在的分子机制，并与新的前列腺素改善剂（Nec-1 s和GSK'772）及其无活性类似物（Nec-1 i）进行了比较。在Langendorff灌注的大鼠心脏中检查心脏功能。某些蛋白调节心肌收缩-舒张周期和氧化应激（OS）进行了评估，通过免疫印迹和脂质过氧化，蛋白质羰基化和硝化的程度，分别。尽管由于Nec-1和Nec-1 i治疗导致左心室发展压（LVDP）增加，但只有前者药物增加了Ca 2 +/钙调蛋白依赖性蛋白激酶II δ（CaMKIIδ）在苏氨酸287和心肌肌球蛋白结合蛋白C（cMyBPc）在丝氨酸282的磷酸化。相比之下，Nec-1 s没有引起这种变化，但也增加了LVDP。GSK'772激活CaMKIIδ-受磷蛋白（PLN）轴。无论是蛋白激酶A（PKA）还是其选定的分子靶点，如丝氨酸16磷酸化PLN和肌浆网/内质网Ca 2 +-ATP酶2a（SERCA 2a），都不受RIP 1抑制剂的影响。Nec-1与其他necrostatin（Nec-1 i，Nec-1 s）一样，而不是GSK'772，在不影响OS的其他标志物的情况下升高蛋白质酪氨酸硝化。总之，本研究首次表明，Nec-1可能通过调节OS和激活收缩-舒张周期的一些蛋白质来影响基础心脏功能。
Inhibition of receptor-interacting protein kinase 1 (RIP1) has been recognized as a compelling tool for limiting necroptosis. Recent findings have indicated that RIP1 inhibitor, necrostatin-1 (Nec-1), is also able to modify heart function under non-cell death conditions. In this study, we investigated its underlying molecular mechanisms and compared with those of novel pharmacologically improved agents (Nec-1s and GSK’772) and its inactive analog (Nec-1i). Heart function was examined in Langendorff-perfused rat hearts. Certain proteins regulating myocardial contraction–relaxation cycle and oxidative stress (OS) were evaluated by immunoblotting and as the extent of lipid peroxidation, protein carbonylation and nitration, respectively. In spite of the increase of left ventricular developed pressure (LVDP) due to treatment by both Nec-1 and Nec-1i, only the former agent increased the phosphorylation of Ca2+/calmodulin-dependent protein kinase II delta (CaMKIIδ) at threonine 287 and cardiac myosin-binding protein-C (cMyBPc) at serine 282. In contrast, Nec-1s did not elicit such changes, while it also increased LVDP. GSK’772 activated CaMKIIδ-phospholamban (PLN) axis. Neither protein kinase A (PKA) nor its selected molecular targets, such as serine 16 phosphorylated PLN and sarco/endoplasmic reticulum Ca2+-ATPase 2a (SERCA2a), were affected by either RIP1 inhibitor. Nec-1, like other necrostatins (Nec-1i, Nec-1s), but not GSK’772, elevated protein tyrosine nitration without affecting other markers of OS. In conclusion, this study indicated for the first time that Nec-1 may affect basal heart function by the modulation of OS and activation of some proteins of contraction–relaxation cycle.