Underexpression of CACNA1C Caused by Overexpression of microRNA-29a Underlies the Pathogenesis of Atrial Fibrillation

Abstract

BackgroundThe objective of this study was to investigate the molecular mechanism of atrial fibrillation (AF), as well as the negative regulatory relationship between miR-29a-3p and CACNA1C.Material/MethodsWe searched the online miRNA database (www.mirdb.org) and identified the miR-29a-3p binding sequence within the 3′-UTR of the target gene, and then conducted luciferase assay to verify it. The cells were transfected with miR-29a-3p and ICa,L was determined in those cells.ResultsWe validated CACNA1C to be the direct target gene of miR-29a-3p. We also established the negative regulatory relationship between miR-29a-3p and CACNA1C via studying the relative luciferase activity. We also conducted real-time PCR and Western blot analysis to study the mRNA and protein expression level of CACNA1C among different groups of cells treated with scramble control, 30nM miR-29a-3p mimics, and 60nM miR-29a-3p mimics, indicating a negative regulatory relationship between miR-29a-3p and CACNA1C. We next analyzed whether miR-29a-3p transfection in cardiomyocytes produced the effects on the ICa,L induced by electrical remodeling, and found a tonic inhibition of IBa by endogenous miR-29a-3p in atrial myocytes.ConclusionsWe validated the negative regulation between miR-29a-3p and CACNA1C, and found that miR-29a-3p might a potential therapeutic target in the treatment of AF.

Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

“…For example, the nicotinamide adenine dinucleotide phosphate oxidases (NOX) 2/4, resulting in a rapid (i.e., over hours or days) reduction of Ca 2+ current L (ICa, L) and the Rectifier K + inward current (IK1) increase, resulting in shortening of APD and the refractory period, supporting rotor formation and stabilization [49]. Reduction of the density of Cav1.2 is the hallmark of the electrical remodeling [50].…”

“…The miR-29a-3p levels are dramatically increased and CACNA1C mRNA levels decreased in atrial tissues with AF compared to those without AF. The atrial myocytes exposed to 30 nM or 60nM of miR-29a-3p mimics having significantly lower levels of the CACNA1C protein [50]. Different mechanisms of AF influenced by miRNAs are summarized in Table 1.…”

The CaMKII phosphorylation site Thr1604 in the CaV1.2 channel is involved in pathological myocardial hypertrophy in rats

“…In addition to regulating cardiomyocyte contraction, Ca 2+ influx from the Ca V 1.2 channel is also involved in intracellular signaling and the gene regulatory events that underlie cardiac hypertrophy and disease [3,4]. Mutations in CACNA1C, which encodes Ca V 1.2, result in the pathogenesis of atrial fibrillation [5], ventricular fibrillation [6], hypertrophic cardiomyopathy [7] and ventricular hypertrophy [8]. Furthermore, Ca V 1.2 is modified posttranslationally (e.g.…”

The Use of Mineralocorticoid Receptor Antagonists in the Pre Vention of Atrial Fibrillation

“…Многочисленные свидетельства важной роли альдостерона в ремоделировании предсердий и развитии ФП [7,31,32] дают основания предполагать, что применение антагонистов МКР может предотвращать возникновение новых случаев либо рецидивов этой аритмии. Действительно, накоплено немало экспериментальных данных [33][34][35][36][37] о благоприятном влиянии антагонистов МКР на процессы структурного ремоделирования предсердий. В экпериментальных моделях постоянной формы ФП спиронолактон уменьшал выраженность апоптоза кардиомиоцитов, клеточной дегенерации, фиброзирования предсердий и способствовал поддержанию функциональных параметров, в частности ФВ ЛП [35].…”

“…Действительно, накоплено немало экспериментальных данных [33][34][35][36][37] о благоприятном влиянии антагонистов МКР на процессы структурного ремоделирования предсердий. В экпериментальных моделях постоянной формы ФП спиронолактон уменьшал выраженность апоптоза кардиомиоцитов, клеточной дегенерации, фиброзирования предсердий и способствовал поддержанию функциональных параметров, в частности ФВ ЛП [35]. Эти данные убедительно показывают, что блокада МКР представляет собой мощную терапевтическую стратегию и в сочетании с применением ингибиторов АПФ или АРА-2 может способствовать сохранению структуры и функции предсердий на фоне ФП.…”