The two-pore K(+) channel TREK-1 regulates pressure overload-induced cardiac remodeling.

Heart failure (HF) represents a major burden on the healthcare system, with patients with HF at increased risk for a host of comorbidities, including ventricular arrhythmias. Despite considerable advances in defining cell- and organ-level changes associated with HF, the precise mechanisms driving structural and electrical remodeling remain to be defined. We sought to elucidate the role of the two-pore K(+) channel TREK-1 in cardiac remodeling in pressure overload-induced HF. Cardiac-specific TREK-1 conditional knockout (TREK1cKO) and floxed control mice were subjected to transaortic contraction (TAC) or sham procedure and evaluated for 6 wk by echocardiography and subsurface electrocardiograms. Ventricular myocytes were isolated for action potential, intracellular Ca(2+), and contractility measurements. The expression/regulation of key cell signaling pathways was evaluated early in remodeling. TREK1cKO and control mice showed a significant decrease in cardiac systolic function with evidence of hypertrophy as early as 2 wk post-TAC compared with sham. However, TREK1cKO mice displayed a more severe decline in function with enhanced left ventricular chamber dilation (eccentric remodeling) compared with control 6 wk post-TAC. Similarly, TAC TREK1cKO mice demonstrated greater prolongation of the QT and QRS intervals compared with TAC control. TAC TREK1cKO ventricular myocytes exhibited greater action potential prolongation with paradoxical improvements in Ca(2+) homeostasis and contractility compared with control. Two weeks post-TAC, TREK1cKO hearts exhibited elevation of STAT3 phosphorylation at Y705 compared with control. Our findings reveal a complex interaction between chronic stress, TREK-1, STAT3 regulation, and cardiac remodeling, with TREK-1 exerting both maladaptive and protective effects on overall cardiac function.NEW & NOTEWORTHY A major finding of this study is the involvement of the background K(+) channel TREK-1 in modulating STAT3 activation, profibrotic gene expression, and fibrosis with implications for the cardiac remodeling response to chronic pressure overload.