著者

Fikri Taufiq Peili Li Junichiro Miake Ichiro Hisatome

出版者

The Japanese Circulation Society

雑誌

Circulation Reports (ISSN:24340790)

巻号頁・発行日

vol.1, no.11, pp.469-473, 2019-11-08 (Released:2019-11-08)

参考文献数

54

被引用文献数

8

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Among the several independent risk factors for atrial fibrillation (AF), hyperuricemia has been widely accepted as associated with the incidence of paroxysmal or persistent AF, as well as with the risk of AF in patients undergoing cardiovascular surgery. The electrophysiological mechanism of AF involves electrical remodeling of the arrhythmogenic substrate and abnormal automaticity as trigger. Both electrical and structural remodeling mediated by oxidative stress derived from either xanthine oxidoreductase (XOR), soluble uric acid (UA) or monosodium urate (MSU) crystals might be plausible explanations for the association of AF with hyperuricemia. XOR generates reactive oxygen species (ROS) that lead to atrial structural remodeling via inflammation. Soluble UA accumulates intracellularly through UA transporters (UAT), shortening the atrial action potential via enhanced expression and activity of Kv1.5 channel proteins. Intracellular accumulation of soluble UA generates ROS in atrial myocytes via nicotinamide adenine dinucleotide phosphate oxidase, which phosphorylates ERK/Akt and heat shock factor 1 (HSF1), thereby increasing transcription and translation of Hsp70, which stabilizes Kv1.5. In macrophages, MSU activates the NLRP3 inflammasome and proteolytic processing mediated by caspase-1 with enhanced interleukin (IL)-1β and IL-18 secretion. Use of an XOR inhibitor, antioxidants, a UAT inhibitor such as a uricosuric agent, and an NLRP3 inflammasome inhibitor, might become a potential strategy to reduce the risk of hyperuricemia-induced AF, and control serum UA level.

著者

Hiroshi Fujii Yu Ikeuchi Yasutaka Kurata Nobuhito Ikeda Udin Bahrudin Peili Li Yuji Nakayama Ryo Endo Akira Hasegawa Kumi Morikawa Junichiro Miake Akio Yoshida Kyoko Hidaka Takayuki Morisaki Haruaki Ninomiya Yasuaki Shirayoshi Kazuhiro Yamamoto Ichiro Hisatome

出版者

日本循環器学会

雑誌

Circulation Journal (ISSN:13469843)

巻号頁・発行日

pp.CJ-12-0126, (Released:2012-09-04)

参考文献数

27

被引用文献数

3 2

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Background: The prion protein (PrP) has been reported to serve as a surface maker for isolation of cardiomyogenic progenitors from murine embryonic stem (ES) cells. Although PrP-positive cells exhibited automaticity, their electrophysiological characteristics remain unresolved. The aim of the present study was therefore to investigate the electrophysiological properties of PrP-positive cells in comparison with those of HCN4p-or Nkx2.5-positive cells. Methods and Results: Differentiation of AB1, HCN5p-EGFP and hcgp7 ES cells into cardiac progenitors was induced by embryoid body (EB) formation. EBs were dissociated and cells expressing PrP, HCN4-EGFP and/or Nkx2.5-GFP were collected via flow cytometry. Sorted cells were subjected to reverse transcriptase-polymerase chain reaction, immunostaining and patch-clamp experiments. PrP-positive cells expressed mRNA of undifferentiation markers, first and second heart field markers, and cardiac-specific genes and ion channels, indicating their commitment to cardiomyogenic progenitors. PrP-positive cells with automaticity showed positive and negative chronotropic responses to isoproterenol and carbamylcholine, respectively. Hyperpolarization-activated cation current (If) was barely detectable, whereas Na+ and L-type Ca2+ channel currents were frequently observed. Their spontaneous activity was slowed by inhibition of sarcoplasmic reticulum Ca2+ uptake and release but not by blocking If. The maximum diastolic potential of their spontaneous firings was more depolarized than that of Nkx2.5-GFP-positive cells. Conclusions: PrP-positive cells contained cardiac progenitors that separated from the lineage of sinoatrial node cells. PrP can be used as a marker to enrich nascent cardiac progenitors.