| First Author | Duan W | Year | 2020 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 318 |
| Issue | 3 | Pages | H566-H580 |
| PubMed ID | 31977249 | Mgi Jnum | J:290344 |
| Mgi Id | MGI:6435939 | Doi | 10.1152/ajpheart.00739.2018 |
| Citation | Duan W, et al. (2020) TASK-1 and TASK-3 channels modulate pressure overload-induced cardiac remodeling and dysfunction. Am J Physiol Heart Circ Physiol 318(3):H566-H580 |
| abstractText | 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-gamma coactivator-1alpha (PGC-1alpha) 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.NEW & NOTEWORTHY 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-gamma coactivator-1 (PGC-1) transcription factor. These data suggest that TASK channels influence the development of cardiac hypertrophy and dysfunction in response to injury. |
