Roy Sashwati, Banerjee Jaideep, Gnyawali Surya C, Khanna Savita, He Guanglong, Pfeiffer Douglas, Zweier Jay L, Sen Chandan K
Davis Heart and Lung Research Institute and Department of Surgery, The Ohio State University Medical Center, Columbus, Ohio, United States of America.
PLoS One. 2013 Jun 19;8(6):e66789. doi: 10.1371/journal.pone.0066789. Print 2013.
Dicer endonuclease, critical for maturation of miRNAs, is depleted in certain forms of cardiomyopathy which results in differential expression of certain microRNAs. We sought to elucidate the mechanisms underlying the rapid loss of cardiac function following cardiac-specific Dicer depletion in adult mice.
Conditional Dicer deletion in the adult murine myocardium demonstrated compromised heart function, mitochondrial dysfunction and oxidant stress. Elevated miR-15b was observed as an early response to Dicer depletion and was found to silence Pim-1 kinase, a protein responsible for maintaining mitochondrial integrity and function. Anti-miRNA based suppression of induced miRNA-15b rescued the function of Dicer-depleted adult heart and attenuated hypertrophy.
Anti-miRNA based suppression of inducible miRNA-15b can prevent rapid loss of cardiac function in a Dicer-depleted adult heart and can be a key approach worthy of therapeutic consideration.
Dicer核酸内切酶对微小RNA(miRNA)的成熟至关重要,在某些形式的心肌病中会减少,这导致某些微小RNA的差异表达。我们试图阐明成年小鼠心脏特异性Dicer缺失后心脏功能迅速丧失的潜在机制。
成年小鼠心肌中条件性Dicer缺失表现为心脏功能受损、线粒体功能障碍和氧化应激。观察到miR-15b升高是对Dicer缺失的早期反应,并且发现其使Pim-1激酶沉默,Pim-1激酶是一种负责维持线粒体完整性和功能的蛋白质。基于抗miRNA对诱导型miRNA-15b的抑制挽救了Dicer缺失的成年心脏的功能并减轻了肥大。
基于抗miRNA对诱导型miRNA-15b的抑制可预防Dicer缺失的成年心脏中心脏功能的快速丧失,并且可能是值得治疗考虑的关键方法。