Mkk4 Is a Negative Regulator of the Transforming Growth Factor Beta 1 Signaling Associated With Atrial Remodeling and Arrhythmogenesis With Age

Abstract

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.

Thioredoxin reverses age-related hypertension by chronically improving vascular redox and restoring eNOS function

“…High amounts of TRX induce mitogen-activated protein ki-nase kinase 4 (MKK4) activation in endothelial cells (41). In addition, MKK4 is a negative regulator of transforming growth factor–β (TGFβ) signaling in endothelial cells (51). Because TGFβ signaling is involved in arterial aging due to MMP-2 (matrix metalloproteinase–2)–TβRII (TGFβ receptor II) signaling that is implicated in age-associated arterial stiffness, activation of MKK4 would decrease TGFβ-MMP2-TβRII pathway activity, resulting in decreased extracellular matrix protein breakdown, decreased arterial stiffness, and improved relaxation.…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…As discussed in earlier sections, TGF-␤1 is a key player in mediating fibrosis, and recent evidence has highlighted MKK4 as a negative regulator of TGF-␤1. MKK4-deficient mice show susceptibility to atrial remodeling and arrythmogenesis and primary cultured cardiomyocytes stimulated with ANG II show increased TGF-␤1 induction (210). Furthermore, rapid atrial pacing suppresses Smad7, a negative regulator of TGF-␤1, through an ANG II/AT 1 R-dependent TGF-␤1 and ERK/Smad2/3 signaling mechanism that activates the Arkadia ubiquitin proteasome pathway.…”

Improving Atrial Fibrillation Therapy

“…A central feature of age-related fibrosis is up-regulation of transforming growth factor beta (TGF-β) (48). Kunamalla et al (27) attempted gene-therapy-based modulation of atrial fibrosis by delivering a dominant-negative type II TGF-β receptor to the posterior left atrium in a canine model of AF.…”