MK5 haplodeficiency attenuates hypertrophy and preserves diastolic function during remodeling induced by chronic pressure overload in the mouse heart
American Journal of Physiology. Heart and Circulatory Physiology
BG. MK5 haplodeficiency attenuates hypertrophy and preserves diastolic function during remodeling induced by chronic pressure overload in the mouse heart. activated protein kinase-5 (MK5) is a protein serine/threonine kinase that is activated by p38 MAPK and the atypical MAPKs ERK3 and ERK4. The physiological function(s) of MK5 remains unknown. Here, we examined the effect of MK5 haplodeficiency on cardiac function and myocardial remodeling. At 12 wk of age, MK5 haplodeficient mice (MK5 ϩ/Ϫ )
... t mice (MK5 ϩ/Ϫ ) were smaller than age-matched wild-type littermates (MK5 ϩ/ϩ ), with similar diastolic function but reduced systolic function. Transverse aortic constriction (TAC) was used to induce chronic pressure overload in 12-wk-old male MK5 ϩ/Ϫ and MK5 ϩ/ϩ mice. Two weeks post-TAC, heart weight-to-tibia length ratios were similarly increased in MK5 ϩ/Ϫ and MK5 ϩ/ϩ hearts, as was the abundance of B-type natriuretic peptide and ␤-myosin heavy chain mRNA. Left ventricular ejection fraction was reduced in both MK5 ϩ/ϩ and MK5 ϩ/Ϫ mice, whereas regional peak systolic tissue velocities were reduced and isovolumetric relaxation time was prolonged in MK5 ϩ/ϩ hearts but not in MK5 ϩ/Ϫ hearts. The TAC-induced increase in collagen type 1-␣ 1 mRNA observed in MK5 ϩ/ϩ hearts was markedly attenuated in MK5 ϩ/Ϫ hearts. Eight weeks post-TAC, systolic function was equally impaired in MK5 ϩ/ϩ and MK5 ϩ/Ϫ mice. In contrast, the increase in E wave deceleration rate and progression of hypertrophy observed in TAC MK5 ϩ/ϩ mice were attenuated in TAC MK5 ϩ/Ϫ mice. MK5 immunoreactivity was detected in adult fibroblasts but not in myocytes. MK5 ϩ/ϩ , MK5 ϩ/Ϫ , and MK5 Ϫ/Ϫ fibroblasts all expressed ␣-smooth muscle actin in culture. Hence, reduced MK5 expression in cardiac fibroblasts was associated with the attenuation of both hypertrophy and development of a restrictive filling pattern during myocardial remodeling in response to chronic pressure overload. NEW & NOTEWORTHY MAPK-activated protein kinase-5 (MK5)/p38-regulated/activated protein kinase is a protein serine/ threonine kinase activated by p38 MAPK and/or the atypical MAPKs ERK3 and ERK4. MK5 immunoreactivity was detected in adult ventricular fibroblasts but not in myocytes. MK5 haplodeficiency attenuated the progression of hypertrophy, reduced collagen type 1 mRNA, and protected diastolic function in response to chronic pressure overload. MAPK-activated protein kinase-5; p38-regulated/activated protein kinase; cardiac remodeling; hypertrophy; fibroblast; pressure overload; p38 mitogen-activated protein kinase * S. A. Nawaito and D. Dingar contributed equally to this work.