MicroRNA-22 Regulates Cardiac Hypertrophy and Remodeling in Response to Stress

Abstract

Rationale The adult heart is composed primarily of terminally differentiated, mature cardiomyocytes that express signature genes related to contraction. In response to mechanical or pathological stress, the heart undergoes hypertrophic growth, a process defined as an increase in cardiomyocyte cell size without an increase in cell number. However, the molecular mechanism of cardiac hypertrophy is not fully understood. Objective To identify and characterize microRNAs that regulate cardiac hypertrophy and remodeling. Methods and Results Screening for muscle-expressed microRNAs that are dynamically regulated during muscle differentiation and hypertrophy identified microRNA-22 (miR-22) as a cardiac- and skeletal muscle–enriched microRNA that is upregulated during myocyte differentiation and cardiomyocyte hypertrophy. Overexpression of miR-22 was sufficient to induce cardiomyocyte hypertrophy. We generated mouse models with global and cardiac-specific miR-22 deletion, and we found that cardiac miR-22 was essential for hypertrophic cardiac growth in response to stress. miR-22–null hearts blunted cardiac hypertrophy and cardiac remodeling in response to 2 independent stressors: isoproterenol infusion and an activated calcineurin transgene. Loss of miR-22 sensitized mice to the development of dilated cardiomyopathy under stress conditions. We identified Sirt1 and Hdac4 as miR-22 targets in the heart. Conclusions Our studies uncover miR-22 as a critical regulator of cardiomyocyte hypertrophy and cardiac remodeling.

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…Like in obesity [57], it is caused by elevated miRNA-34a [106,184], a proposed brain ageing marker [108] which is capable of modulating cellular senescence [9,83]. A similar effect on senescence has been noted for other microRNAs that target Sirt1: miRNA-22 [81,241] and miRNA-217 [129]. Sirt-1 reduction by up-regulated miRNA (miR-181) also occurs in the hippocampus of a mouse AD model (3×Tg) [170].…”

Regulation of PP2Cm expression by miRNA-204/211 and miRNA-22 in mouse and human cells

“…org). Finally, miR-22 is fully conserved between human and mouse and has been reported to be involved in cardiovascular diseases and metabolic regulation [25][26][27] . Although PP2Cm performs crucial roles in cells, little is known about the regulatory mechanism of PPM1K gene expression.…”

How to be young at heart? miR-22 as a potential therapeutic target to boost autophagy and protect the old myocardium

“…Mice with either systemic or cardiac-specific miR-22 gene deletion do not develop compensatory hypertrophy in response to isoproterenol treatment and display increased cardiac dilation and dysfunction with respect to control mice (16). Similarly, systemic miR-22 knockout mice were found to develop cardiac dilation and dysfunction in response to pressure overload (17).…”