miR-1 mediated suppression of Sorcin regulates myocardial contractility through modulation of Ca2+ signaling.
MicroRNAs are negative gene regulators and play important roles in cardiac development and disease. As evident by cardiomyopathy following cardiac-specific Dicer knockdown they also are required for maintaining normal cardiac contractile function but the specific role of miR-1 in the process is poorly understood. To characterize the role of miR-1 in particular and to identify its specific targets we created a tamoxifen-inducible, cardiac-specific Dicer knockdown mouse and demonstrated that Dicer downregulation results in a dramatic and rapid decline in cardiac function concurrent with significantly reduced levels of miR-1. The importance of miR-1 was established by miR-1 antagomir treatment of wild-type mice, which replicated the cardiac-specific Dicer knockdown phenotype. Down-regulation of miR-1 was associated with up-regulation of its predicted target Sorcin, an established modulator of calcium signaling and excitation-contraction coupling, subsequently verified as a miR-1 target with luciferase constructs. siRNA-mediated knockdown of Sorcin effectively rescued the cardiac phenotypes after Dicer or miR-1 knockdown affirming Sorcin as a critical mediator of the acute cardiomyopathy observed. The regulatory relationship between miR-1 and Sorcin was further confirmed in cultured mouse cardiomyocytes where modulation of miR-1 was associated with discordant Sorcin levels and dysregulation of calcium signaling. Pathological relevance of our findings included decreased miR-1 and increased Sorcin expression in end-stage cardiomyopathy. These findings demonstrate the importance of miR-1 in cardiac function and in the pathogenesis of heart failure via Sorcin-dependent calcium homeostasis.
Section of Cardiac Surgery, Department of Surgery, Yale University, New Haven, CT 06510, USA.
Rahmat
R
Ali
Yan
Y
Huang
Stephen E
SE
Maher
Richard W
RW
Kim
Frank J
FJ
Giordano
George
G
Tellides
Arnar
A
Geirsson
D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002306:Cardiac Volume / Q000235:genetics; D009202:Cardiomyopathies / Q000378:metabolism; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics; D006321:Heart / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009200:Myocardial Contraction / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D015854:Up-Regulation
D002135:Calcium-Binding Proteins; D035683:MicroRNAs; C517731:Mirn1 microRNA, mouse; D034741:RNA, Small Interfering; C503114:Sri protein, mouse; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases