Department of Medicine, Duke University Medical Center, Durham, North Carolina.
DOCS Global, Durham, North Carolina.
Am J Physiol Heart Circ Physiol. 2020 Mar 1;318(3):H566-H580. doi: 10.1152/ajpheart.00739.2018. Epub 2020 Jan 24.
Tandem pore domain acid-sensitive K (TASK) channels are present in cardiac tissue; however, their contribution to cardiac pathophysiology is not well understood. Here, we investigate the role of TASK-1 and TASK-3 in the pathogenesis of cardiac dysfunction using both human tissue and mouse models of genetic TASK channel loss of function. Compared with normal human cardiac tissue, TASK-1 gene expression is reduced in association with either cardiac hypertrophy alone or combined cardiac hypertrophy and heart failure. In a pressure overload cardiomyopathy model, TASK-1 global knockout (TASK-1 KO) mice have both reduced cardiac hypertrophy and preserved cardiac function compared with wild-type mice. In contrast to the TASK-1 KO mouse pressure overload response, TASK-3 global knockout (TASK-3 KO) mice develop cardiac hypertrophy and a delayed onset of cardiac dysfunction compared with wild-type mice. The cardioprotective effects observed in TASK-1 KO mice are associated with pressure overload-induced augmentation of AKT phosphorylation and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, with consequent augmentation of cardiac energetics and fatty acid oxidation. The protective effects of TASK-1 loss of function are associated with an enhancement of physiologic hypertrophic signaling and preserved metabolic functions. These findings may provide a rationale for TASK-1 channel inhibition in the treatment of cardiac dysfunction. The role of tandem pore domain acid-sensitive K (TASK) channels in cardiac function is not well understood. This study demonstrates that TASK channel gene expression is associated with the onset of human cardiac hypertrophy and heart failure. TASK-1 and TASK-3 strongly affect the development of pressure overload cardiomyopathies in genetic models of TASK-1 and TASK-3 loss of function. The effects of TASK-1 loss of function were associated with enhanced AKT phosphorylation and expression of peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury.
TASK 通道是存在于心肌组织中的串联孔域酸敏感钾通道；然而，其在心脏病理生理学中的作用尚未被充分理解。在此，我们使用人类组织和遗传 TASK 通道功能丧失的小鼠模型，研究了 TASK-1 和 TASK-3 在心脏功能障碍发病机制中的作用。与正常人类心脏组织相比，TASK-1 基因表达在单纯心肌肥厚或心肌肥厚合并心力衰竭时均降低。在压力超负荷性心肌病模型中，与野生型小鼠相比，TASK-1 全局敲除（TASK-1 KO）小鼠的心肌肥厚减少，心脏功能得到保留。与 TASK-1 KO 小鼠的压力超负荷反应相反，TASK-3 全局敲除（TASK-3 KO）小鼠与野生型小鼠相比，发生心肌肥厚和心脏功能障碍的发生延迟。在 TASK-1 KO 小鼠中观察到的心脏保护作用与压力超负荷诱导的 AKT 磷酸化和过氧化物酶体增殖物激活受体-γ 共激活因子-1α（PGC-1α）表达增强有关，进而增强了心脏能量代谢和脂肪酸氧化。TASK-1 功能丧失的保护作用与生理性肥大信号的增强和代谢功能的保留有关。这些发现可能为 TASK-1 通道抑制治疗心脏功能障碍提供了依据。TASK 通道在心脏功能中的作用尚未被充分理解。本研究表明，TASK 通道基因表达与人类心肌肥厚和心力衰竭的发生有关。在 TASK-1 和 TASK-3 功能丧失的遗传模型中，TASK-1 和 TASK-3 强烈影响压力超负荷性心肌病的发展。TASK-1 功能丧失的作用与 AKT 磷酸化增强和过氧化物酶体增殖物激活受体-γ 共激活因子-1（PGC-1）转录因子的表达有关。这些数据表明，TASK 通道影响损伤后心肌肥厚和功能障碍的发展。
