MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice.
MicroRNAs (miRNAs) are a class of small noncoding RNAs that have gained status as important regulators of gene expression. Here, we investigated the function and molecular mechanisms of the miR-208 family of miRNAs in adult mouse heart physiology. We found that miR-208a, which is encoded within an intron of alpha-cardiac muscle myosin heavy chain gene (Myh6), was actually a member of a miRNA family that also included miR-208b, which was determined to be encoded within an intron of beta-cardiac muscle myosin heavy chain gene (Myh7). These miRNAs were differentially expressed in the mouse heart, paralleling the expression of their host genes. Transgenic overexpression of miR-208a in the heart was sufficient to induce hypertrophic growth in mice, which resulted in pronounced repression of the miR-208 regulatory targets thyroid hormone-associated protein 1 and myostatin, 2 negative regulators of muscle growth and hypertrophy. Studies of the miR-208a Tg mice indicated that miR-208a expression was sufficient to induce arrhythmias. Furthermore, analysis of mice lacking miR-208a indicated that miR-208a was required for proper cardiac conduction and expression of the cardiac transcription factors homeodomain-only protein and GATA4 and the gap junction protein connexin 40. Together, our studies uncover what we believe are novel miRNA-dependent mechanisms that modulate cardiac hypertrophy and electrical conduction.
Callis
Thomas E
TE
Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, North Carolina, USA.
Pandya
Kumar
K
Seok
Hee Young
HY
Tang
Ru-Hang
RH
Tatsuguchi
Mariko
M
Huang
Zhan-Peng
ZP
Chen
Jian-Fu
JF
Deng
Zhongliang
Z
Gunn
Bronwyn
B
Shumate
Janelle
J
Willis
Monte S
MS
Selzman
Craig H
CH
Wang
Da-Zhi
DZ
D000818:Animals; D001483:Base Sequence; D024722:Cardiac Myosins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D006321:Heart / Q000254:growth & development; D006329:Heart Conduction System / Q000502:physiology*; D007438:Introns; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D018995:Myosin Heavy Chains / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D017931:DNA Primers; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; D011993:Recombinant Fusion Proteins; D024722:Cardiac Myosins; D018995:Myosin Heavy Chains