Abstract
BackgroundDicer 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.ResultsConditional 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.ConclusionsAnti-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.
Highlights
Arrest of miRNA maturation by targeted deletion of Dicer is known to perturb cardiac development [1,2] and cause pathological consequences [3,4]
To dissect the significance of Dicer in mammalian biology, several groups have disrupted the Dicer gene in different organs in mice [23,24].http://circres.ahajournals.org/cgi/content/full/100/8/ 1164 - R25-M150524#R25-M150524 Cardiac-specific deletion of Dicer leads to defects in heart development and embryonic lethality [1,4], demonstrating that Dicer is necessary for murine development
In order to study the effects of Dicer depletion in adult heart, we developed a double transgenic Myh6-cre/Esr1Dicerfl/fl mice by breeding mice with a floxed Dicer allele [25] with mice expressing a tamoxifen-inducible Cre recombinase protein, flanked on each end with a mutated murine estrogen receptor ligand binding domain, under the control of the cardiac-specific murine alpha-myosin heavy chain (Myh6) promoter
Summary
Arrest of miRNA maturation by targeted deletion of Dicer is known to perturb cardiac development [1,2] and cause pathological consequences [3,4] Significance of such observations is heightened by the report that Dicer deficiency is associated with specific forms of cardiomyopathy and heart failure in humans [4]. Our strategy has been to delineate primary causative mechanisms by focusing on early onset changes in the adult heart following Dicer deletion, with the goal to be able to rescue using miRNAdirected intervention. This approach resulted in the identification of elevated miRNA-15b in the heart as a causative factor. We sought to elucidate the mechanisms underlying the rapid loss of cardiac function following cardiac-specific Dicer depletion in adult mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
