目的:由于运动而发生生理性心肌肥厚,对病理性应激有保护作用。相比之下,病理性肥大发生在疾病中,通常先于心力衰竭。在生理和病理性肥大中激活的心脏途径在很大程度上是不同的。我们先前的工作表明,miR-222在运动心脏中增加,并且是运动诱导的心脏肥大和心肌形成所必需的。这里,我们试图确定miR-222在病理性肥大中的作用.
结果:我们发现miR-222在压力超负荷诱导的病理性肥大中也增加。为了评估其在此设置中的功能意义,我们通过心脏特异性组成型转基因miR-222表达(TgC-miR-222)建立了miR-222功能获得模型,并使用miR-222特异性的锁核酸抗miR抑制其作用.功能恢复和功能丧失模型均在基线时表现出正常的心脏结构和功能。然而,主动脉横缩窄(TAC)后,miR-222抑制加速病理性肥大的发展,心功能不全,和心力衰竭。相反,过表达miR-222的小鼠在TAC后病理性肥大较少,以及更好的心脏功能和存活率。我们鉴定了p53上调的凋亡调节剂,促凋亡Bcl-2家族成员,和转录因子,Hmbox1和活化T细胞的核因子3,作为miR-222的直接靶标,有助于其在这种情况下的作用。
结论:虽然miR-222是生理心脏生长所必需的,它抑制了对压力超负荷的反应的心脏生长,并减少了不良的重塑和心脏功能障碍。这些发现支持生理和病理肥大根本不同的模型。Further,他们提示miR-222有望作为病理性心肌肥厚和心力衰竭的治疗靶点.
Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy.
We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context.
While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.