Casein Kinase-2 Interacting Protein-1 Regulates Physiological Cardiac Hypertrophy via Inhibition of Histone Deacetylase 4 Phosphorylation

Abstract

Different kinds of mechanical stimuli acting on the heart lead to different myocardial phenotypes. Physiological stress, such as exercise, leads to adaptive cardiac hypertrophy, which is characterized by a normal cardiac structure and improved cardiac function. Pathological stress, such as sustained cardiac pressure overload, causes maladaptive cardiac remodeling and, eventually, heart failure. Casein kinase-2 interacting protein-1 (CKIP-1) is an important regulator of pathological cardiac remodeling. However, the role of CKIP-1 in physiological cardiac hypertrophy is unknown. We subjected wild-type (WT) mice to a swimming exercise program for 21 days, which caused an increase in myocardial CKIP-1 protein and mRNA expression. We then subjected CKIP-1 knockout (KO) mice and myocardial-specific CKIP-1-overexpressing mice to the 21-day swimming exercise program. Histological and echocardiography analyses revealed that CKIP-1 KO mice underwent pathological cardiac remodeling after swimming, whereas the CKIP-1-overexpressing mice had a similar cardiac phenotype to the WT controls. Histone deacetylase 4 (HDAC4) is a key molecule in the signaling cascade associated with pathological hypertrophy; the phosphorylation levels of HDAC4 were markedly higher in CKIP-1 KO mouse hearts after the swimming exercise program. The phosphorylation levels of HDAC4 did not change after swimming in the hearts of CKIP-1-overexpressing or WT mice. Our results indicate that swimming, a mechanical stress that leads to physiological hypertrophy, triggers pathological cardiac remodeling in CKIP-1 KO mice. CKIP-1 is necessary for physiological cardiac hypertrophy in vivo, and for modulating the phosphorylation level of HDAC4 after physiological stress. Genetically engineering CKIP-1 expression affected heart health in response to exercise.

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

“… 390 CKIP‐1 regulates physiological cardiac hypertrophy by inhibiting HDAC4 phosphorylation. 391 In an AngII‐induced mouse model of pathological cardiac hypertrophy, the pan‐HDAC inhibitor (HDACI) emodin ameliorates hypertrophy by inhibiting the activity of class I, IIa, and IIb HDACs. 392 HDACs are also involved in myocardial fibrosis.…”

“…The interaction between SIRT1 and eNOS can activate eNOS by reducing its acetylation level, which promotes NO production and vasodilation 390 . CKIP‐1 regulates physiological cardiac hypertrophy by inhibiting HDAC4 phosphorylation 391 . In an AngII‐induced mouse model of pathological cardiac hypertrophy, the pan‐HDAC inhibitor (HDACI) emodin ameliorates hypertrophy by inhibiting the activity of class I, IIa, and IIb HDACs 392 .…”

Transforming growth factor-β and bone morphogenetic protein signaling pathways in pathological cardiac hypertrophy

“…Somy Yoon et al suggested that PP2A is a critical regulator of pathological cardiac hypertrophy [ 157 ]. The inhibition of pathological cardiac hypertrophy by casein kinase-2 interacting protein-1 (CKIP-1), a regulator of cell proliferation and apoptosis and an important regulator of pathological cardiac remodeling, was achieved by increasing the dephosphorylation of histone deacetylase 4 (HDAC4) through the recruitment of PP2A, and this signaling cascade was associated with pathological hypertrophy [ 155 , 159 ]. The specific mechanisms by which PP2A exerts its antihypertrophic effects via TGF-β to regulate the development of myocardial hypertrophy and the other downstream signaling molecules involved in this signaling pathway need to be further investigated.…”

Effect of eight weeks of swimming training and CBD oil consumption on PI3K and ERK gene expression in the heart tissue of rats with myocardial infarction

“…Cardiovascular diseases lead to incompatible regeneration in heart cells by increasing fibrosis and decreasing aerobic capacity. Some reports have suggested that the PI3K/AKT signaling pathway is an important regulator of cell growth that regulates cell growth and proliferation processes, gene expression, and protein synthesis (5,6). Many studies have indicated that the PI3K enzyme is activated by specific stimuli in the heart, and it plays an important role in regulating heart muscle growth by binding to tyrosine kinase receptors.…”