Key result
ERK3 deficiency attenuates pressure overload-induced cardiac hypertrophy and reduces fibrotic gene expression.
Why the study?
MK5 haplodeficiency reduces hypertrophy and alters cardiac fibroblast function under increased afterload, but the role of upstream ERK3 in cardiac hypertrophy and fibroblast biology was unclear.
ERK3 plays an important role in pathological cardiac remodeling and fibroblast activation, suggesting it may be a key mediator of cardiac fibrosis and hypertrophy.
Hypothesis-generating for ERK3 inhibition in pressure-overload remodeling; leaves open translation to human HF therapy.
ERK3/MAPK6, an atypical MAPK, activates MAP kinase-activated protein kinase (MK)-5 in selected cell types. MK5 haplodeficient mice show reduced hypertrophy and attenuated increase in Col1a1 mRNA in response to increased cardiac afterload. In addition, MK5 deficiency alters cardiac fibroblast function. This study was to determine the effect of reduced ERK3 on cardiac hypertrophy following transverse aortic constriction (TAC) and fibroblast biology. Three wk post-surgery, ERK3, but not ERK4 or p38α, was co-immunoprecipitated with MK5 from both sham and TAC heart lysates. The increase in left ventricular mass and myocyte diameter was lower in TAC-ERK3 +/- than TAC-ERK3 +/+ hearts, whereas ERK3 haploinsufficiency did not alter systolic or diastolic function. Furthermore, the TAC-induced increase in Col1a1 mRNA abundance was diminished in ERK3 +/- hearts. ERK3 immunoreactivity was detected in atrial and ventricular fibroblasts but not myocytes. In both quiescent fibroblasts and ‘activated’ myofibroblasts isolated from adult mouse heart, siRNA-mediated knockdown of ERK3 reduced the TGF-β-induced increase in Col1a1 mRNA. In addition, intracellular type 1 collagen immunoreactivity was reduced following ERK3 depletion in quiescent fibroblasts but not myofibroblasts. Finally, knocking down ERK3 impaired motility in both atrial and ventricular myofibroblasts. These results suggest that ERK3 plays an important role in multiple aspects of cardiac fibroblast biology.
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Sahadevan et al. (2023) studied Cardiac hypertrophy and fibrosis. ERK3 haploinsufficiency or siRNA knockdown vs. Wild-type (ERK3+/+) or scrambled siRNA was evaluated on Cardiac hypertrophy (LV mass, myocyte diameter) and Col1a1 mRNA abundance. ERK3 haploinsufficiency attenuated the increase in left ventricular mass and myocyte diameter following transverse aortic constriction, and ERK3 knockdown reduced TGF-β-induced Col1a1 mRNA expression in cardiac fibroblasts.
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