Scott Xavier O, Kerr Nadine A, Sanchez-Molano Juliana, de Rivero Vaccari Juan Pablo, Hadad Roey, De La Cruz Alicia, Larsson H Peter, Dietrich W Dalton, Keane Robert W
Department of Molecular Physiology and Cellular Biophysics, University of Miami Miller School of Medicine, Miami, FL, USA.
The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, Miami, FL, 33136, USA.
Transl Stroke Res. 2024 Nov 18. doi: 10.1007/s12975-024-01311-3.
Cerebrovascular stroke patients exhibit an increased incidence of cardiac arrhythmias. The pathomechanisms underlying post-traumatic cardiac dysfunction include a surge of catecholamines and an increased systemic inflammatory response, but whether inflammasome activation contributes to cardiac dysfunction remains unexplored. Here, we used a mouse model of photothrombotic stroke (PTS) to investigate the role of inflammasome activation in post-stroke cardiac dysfunction by catecholamines and to evaluate the effectiveness of the inflammasome inhibitor IC100 on inflammasome activation. To evaluate functional electrophysiological changes in the heart by catecholamine treatment, we recorded action potential duration in excised zebrafish hearts with and without IC100 treatment. We show that PTS induced AIM2 inflammasome activation in atria and ventricles that was significantly reduced by administration of IC100. Injection of epinephrine into naïve mice induced a significant increase in AIM2, IL-1b and caspase-8 in atria. Treatment of excised zebrafish hearts with epinephrine shortened the action potential duration and this shortening that was reduced by IC100. These findings indicate that stroke initiates a catecholamine surge that induces inflammasome activation and pyroptosis in the heart that is blocked by IC100, thus providing a framework for the development of therapeutics for stroke-related cardiovascular injury.
脑血管中风患者心律失常的发生率增加。创伤后心脏功能障碍的发病机制包括儿茶酚胺激增和全身炎症反应增加，但炎性小体激活是否导致心脏功能障碍仍未得到探索。在此，我们使用光血栓性中风（PTS）小鼠模型来研究炎性小体激活在儿茶酚胺介导的中风后心脏功能障碍中的作用，并评估炎性小体抑制剂IC100对炎性小体激活的有效性。为了评估儿茶酚胺处理对心脏功能电生理变化的影响，我们记录了在有或没有IC100处理的情况下切除的斑马鱼心脏中的动作电位持续时间。我们发现，PTS诱导心房和心室中的AIM2炎性小体激活，而IC100给药可显著降低这种激活。向未处理的小鼠注射肾上腺素会导致心房中AIM2、IL-1β和半胱天冬酶-8显著增加。用肾上腺素处理切除的斑马鱼心脏会缩短动作电位持续时间，而IC100可减少这种缩短。这些发现表明，中风引发儿茶酚胺激增，诱导心脏中的炎性小体激活和细胞焦亡，而IC100可阻断这种激活，从而为开发中风相关心血管损伤的治疗方法提供了框架。
