TY - JOUR
T1 - Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy
AU - Noyes, Adam M.
AU - Zhou, Anyu
AU - Gao, Ge
AU - Gu, Lianzhi
AU - Day, Sharlene
AU - Andrew Wasserstrom, J.
AU - Dudley, Samuel C.
N1 - Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017/12/15
Y1 - 2017/12/15
N2 - Background Our previous studies showed that in ischemic and nonischemic heart failure (HF), the voltage-gated cardiac Na+ channel α subunit (SCN5A) mRNA is abnormally spliced to produce two truncated transcript variants (E28C and D) that activate the unfolded protein response (UPR). We tested whether SCN5A post-transcriptional regulation was abnormal in hypertrophic cardiomyopathy (HCM). Material and methods Human heart tissue was obtained from HCM patients. The changes in relative abundances of SCN5A, its variants, splicing factors RBM25 and LUC7A, and PERK, a major effector of the UPR, were analyzed by real time RT-PCR and the expression changes were confirmed by Western Blot. Results We found reduced full-length transcript, increased SCN5A truncation variants and activation of UPR in HCM when compared to control hearts. In these patients, real time RT-PCR revealed that HCM patients had decreased SCN5A mRNA to 27.8 ± 4.07% of control (P < 0.01) and an increased abundance of E28C and E28D (3.4 ± 0.3 and 2.8 ± 0.3-fold, respectively, P < 0.05). PERK mRNA increased 8.2 ± 3.1 fold (P < 0.01) in HCM patients. Western blot confirmed a significant increase of PERK. Conclusions These data suggested that the full-length SCN5A was reduced in patients with HCM. This reduction was accompanied by abnormal SCN5A pre-mRNA splicing and UPR activation. These changes may contribute to the arrhythmic risk in HCM.
AB - Background Our previous studies showed that in ischemic and nonischemic heart failure (HF), the voltage-gated cardiac Na+ channel α subunit (SCN5A) mRNA is abnormally spliced to produce two truncated transcript variants (E28C and D) that activate the unfolded protein response (UPR). We tested whether SCN5A post-transcriptional regulation was abnormal in hypertrophic cardiomyopathy (HCM). Material and methods Human heart tissue was obtained from HCM patients. The changes in relative abundances of SCN5A, its variants, splicing factors RBM25 and LUC7A, and PERK, a major effector of the UPR, were analyzed by real time RT-PCR and the expression changes were confirmed by Western Blot. Results We found reduced full-length transcript, increased SCN5A truncation variants and activation of UPR in HCM when compared to control hearts. In these patients, real time RT-PCR revealed that HCM patients had decreased SCN5A mRNA to 27.8 ± 4.07% of control (P < 0.01) and an increased abundance of E28C and E28D (3.4 ± 0.3 and 2.8 ± 0.3-fold, respectively, P < 0.05). PERK mRNA increased 8.2 ± 3.1 fold (P < 0.01) in HCM patients. Western blot confirmed a significant increase of PERK. Conclusions These data suggested that the full-length SCN5A was reduced in patients with HCM. This reduction was accompanied by abnormal SCN5A pre-mRNA splicing and UPR activation. These changes may contribute to the arrhythmic risk in HCM.
KW - Human
KW - Hypertrophic cardiomyopathy
KW - Perk
KW - SCN5A
KW - Sodium channels
KW - Splicing variants
KW - Sudden cardiac death
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U2 - 10.1016/j.ijcard.2017.08.071
DO - 10.1016/j.ijcard.2017.08.071
M3 - Article
C2 - 28916354
AN - SCOPUS:85029149324
SN - 0167-5273
VL - 249
SP - 282
EP - 286
JO - International Journal of Cardiology
JF - International Journal of Cardiology
ER -