CITED4 Protects Against Adverse Remodeling in Response to Physiological and Pathological Stress

Abstract

Rationale: Cardiac CITED4 is induced by exercise and is sufficient to cause physiological hypertrophy and mitigate adverse ventricular remodeling after ischemic injury. However, the role of endogenous CITED4 in response to physiological or pathological stress is unknown. Objective: To investigate the role of CITED4 in murine models of exercise and pressure overload. Methods and Results: We generated cardiomyocyte-specific CITED4 knockout mice (C4KO) and subjected them to an intensive swim exercise protocol as well as transverse aortic constriction (TAC). Echocardiography, western blotting, qPCR, immunohistochemistry, immunofluorescence, and transcriptional profiling for mRNA and miRNA expression were performed. Cellular crosstalk was investigated in vitro. CITED4 deletion in cardiomyocytes did not affect baseline cardiac size or function in young adult mice. C4KO mice developed modest cardiac dysfunction and dilation in response to exercise. After TAC, C4KOs developed severe heart failure with left ventricular dilation, impaired cardiomyocyte growth accompanied by reduced mammalian target of rapamycin (mTOR) activity and maladaptive cardiac remodeling with increased apoptosis, autophagy, and impaired mitochondrial signaling. Interstitial fibrosis was markedly increased in C4KO hearts after TAC. RNAseq revealed induction of a pro-fibrotic miRNA network. miR30d was decreased in C4KO hearts after TAC and mediated crosstalk between cardiomyocytes and fibroblasts to modulate fibrosis. miR30d inhibition was sufficient to increase cardiac dysfunction and fibrosis after TAC. Conclusions: CITED4 protects against pathological cardiac remodeling by regulating mTOR activity and a network of miRNAs mediating cardiomyocyte to fibroblast crosstalk. Our findings highlight the importance of CITED4 in response to both physiological and pathological stimuli.

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

“…The mechanisms by which divergent signaling mechanisms can lead to distinct patterns of pathological and physiological cardiac hypertrophy are still unknown to cardiac biologists ( Wilkins et al, 2004 ; Heineke and Molkentin, 2006 ; Liu et al, 2009 ). Cardiomyocyte-specific deletion of CITED4 in mice causes maladaptive remodeling and functional deficit in response to endurance exercise ( Lerchenmüller et al, 2020 ). Notably, this phenotype differs from typical physiological hypertrophy.…”

Exercise: a molecular tool to boost muscle growth and mitochondrial performance in heart failure?

“…Considering that this pathway signals through miRs, RNA-based therapeutics may offer opportunities to promote physiological growth in HF. 19,23,44,146,147 Another example, of a potential target to regulate physiological growth is A-kinase interacting protein 1 (AKIP1). suggesting potential targets to improve exercise tolerance in HF.…”

Animal exercise studies in cardiovascular research: Current knowledge and optimal design—A position paper of the Committee on Cardiac Rehabilitation, Chinese Medical Doctors’ Association

“… 177 , 178 In in vivo experiments, exercise-associated cardiac phenotypes, such as physiological cardiac hypertrophy (without dysregulation of pathological hypertrophy markers, e.g., atrial natriuretic peptide and brain natriuretic peptide) and increased expression of proliferation markers (e.g., 5-ethynyl-2’-deoxyuridine, Ki-67, phosphohistone H3, and Aurora B) in the myocardium deserve to be validated in exercised animal models such as murine models of swimming exercise by using genetically engineered or modified animals. 92 , 98 , 175 , 179 A deep understanding of the functions and mechanisms of exercise-responsive molecules paves the way for identifying novel myocardial protective or therapeutic targets for CVDs. 8 , 137 , 176 …”