Abnormal sodium channel mRNA splicing in hypertrophic cardiomyopathy. (15th December 2017)

• Record Type: Journal Article
• Authors: Noyes, Adam M.; Zhou, Anyu; Gao, Ge; Gu, Lianzhi; Day, Sharlene; Andrew Wasserstrom, J.; Dudley, Samuel C.
• Is Part Of: International journal of cardiology. Volume 249(2017)
• Page Start: 282
• Page End: 286
• Publication Date: 2017-12-15
• Subjects: Sodium channels -- Hypertrophic cardiomyopathy -- Sudden cardiac death -- Human -- SCN5A -- Perk -- Splicing variants; Cardiology -- Periodicals; Electronic journals; 616.12
• DOI: 10.1016/j.ijcard.2017.08.071
• Languages: English
• ISSNs: 0167-5273

Abstract

Abstract: 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.