Regulation of cardiac CACNB2 by microRNA-499: Potential role in atrial fibrillation.
Regulation of cardiac CACNB2 by microRNA-499: Potential role in atrial fibrillation.
复制标题
DOI：
10.1016/j.bbacli.2017.02.002
复制
发表时间：
2017-06
期刊：
影响因子：
--
通讯作者：
Lee HC
中科院分区：
文献类型：
--
作者：
Ling TY;Wang XL;Chai Q;Lu T;Stulak JM;Joyce LD;Daly RC;Greason KL;Wu LQ;Shen WK;Cha YM;Lee HC
The L-type calcium channel (LTCC) is one of the major ion channels that are known to be associated with the electrical remodeling of atrial fibrillation (AF). In AF, there is significant downregulation of the LTCC, but the underlying mechanism for such downregulation is not clear. We have previously reported that microRNA-499 (miR-499) is significantly upregulated in patients with permanent AF and that KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), is a target of miR-499. We found that CACNB2, an important subunit of the LTCC, is also a target of miR-499. We hypothesize that miR-499 plays an important role in AF electrical remodeling by regulating the expression of CACNB2 and the LTCC. In atrial tissue from patients with permanent AF, CACNB2 was significantly downregulated by 67% (n = 4, p < 0.05) compared to those from patients with no history of AF. Transfection of miR-499 mimic into HL-1 cells, a mouse hyperplastic atrial cardiac myocyte cell-line, resulted in the downregulation of CACNB2 protein expression, while that of miR-499 inhibitor upregulated CACNB2 protein expression. Binding of miR-499 to the 3′ untranslated region of CACNB2 was confirmed by luciferase reporter assay and by the increased presence of CACNB2 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with the miR-499 mimic. In addition, downregulation of CACNB2 resulted in the downregulation of protein levels of the pore-forming α-subunit (CACNA1C). In conclusion, upregulation of atrial miR-499 induces the downregulation of CACNB2 expression and may contribute to the electrical remodeling in AF. LTCC is downregulated with electrical remodeling of atrial fibrillation. MiR-499 is increased and CACNB2 is reduced in atria from patients with atrial fibrillation. MiR-499 binds to the 3′UTR of CACNB2 and inhibits its protein expression. Downregulation of CACNB2 results in the downregulation of LTCC pore-forming subunit. MiR-499 contributes to the electrical remodeling of AF through regulation of CACNB2.
