BackgroundAtrial fibrillation (AF), often associated with structural, fibrotic change in cardiac tissues involving regulatory signaling mediators, becomes increasingly common with age. In the present study, we explored the role of mitogen‐activated protein kinase kinase 4 (Mkk4), a critical component of the stress‐activated mitogen‐activated protein kinase family, in age‐associated AF.Methods and ResultsWe developed a novel mouse model with a selective inactivation of atrial cardiomyocyte Mkk4 (Mkk4ACKO). We characterized and compared electrophysiological, histological, and molecular features of young (3‐ to 4‐month), adult (6‐month), and old (1‐year) Mkk4ACKO mice with age‐matched control littermates (Mkk4F/F). Aging Mkk4ACKO mice were more susceptible to atrial tachyarrhythmias than the corresponding Mkk4F/F mice, showing characteristic slow and dispersed atrial conduction, for which modeling studies demonstrated potential arrhythmic effects. These differences paralleled increased interstitial fibrosis, upregulated transforming growth factor beta 1 (TGF‐β1) signaling and dysregulation of matrix metalloproteinases in Mkk4ACKO, compared to Mkk4F/F, atria. Mkk4 inactivation increased the sensitivity of cultured cardiomyocytes to angiotensin II–induced activation of TGF‐β1 signaling. This, in turn, enhanced expression of profibrotic molecules in cultured cardiac fibroblasts, suggesting cross‐talk between these two cell types in profibrotic signaling. Finally, human atrial tissues in AF showed a Mkk4 downregulation associated with increased production of profibrotic molecules, compared to findings in tissue from control subjects in sinus rhythm.ConclusionsThese findings together demonstrate, for the first time, that Mkk4 is a negative regulator of the TGF‐β1 signaling associated with atrial remodeling and arrhythmogenesis with age, establishing Mkk4 as a new potential therapeutic target for treating AF.

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