Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice

Fuminori Odagiri, Hana Inoue, Masami Sugihara, Takeshi Suzuki, Takashi Murayama, Takao Shioya, Masato Konishi, Yuji Nakazato, Hiroyuki Daida, Takashi Sakurai, Sachio Morimoto, Nagomi Kurebayashi

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Abstract

Inherited dilated cardiomyopathy (DCM) is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF). Although angiotensin receptor blockers (ARBs) have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210). DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t 1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD) in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein), KChIP2 (auxiliary subunit of Kv4.2), and Kv1.5 (I Kur channel protein) in DCM was partially reversed by candesartan administration. Interestingly, nontreated DCM heart had both normal-sized myocytes with moderately decreased I to and I Kur and enlarged cells with greatly reduced K + currents (I to , I Kur I K1 and I ss ). Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the I to , and I Kur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.

Original languageEnglish
Article numbere101838
JournalPloS one
Volume9
Issue number7
DOIs
Publication statusPublished - Jul 7 2014

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Atrial Remodeling
cardiomyopathy
Dilated Cardiomyopathy
animal models
heart
Angiotensin Receptor Antagonists
Kv Channel-Interacting Proteins
angiotensins
heart failure
myocardium
Dilatation
Myocardium
mice
Drinking Water
Heart Failure
candesartan
receptors
arrhythmia
Cardiomegaly
cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Odagiri, F., Inoue, H., Sugihara, M., Suzuki, T., Murayama, T., Shioya, T., ... Kurebayashi, N. (2014). Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice. PloS one, 9(7), [e101838]. https://doi.org/10.1371/journal.pone.0101838

Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice. / Odagiri, Fuminori; Inoue, Hana; Sugihara, Masami; Suzuki, Takeshi; Murayama, Takashi; Shioya, Takao; Konishi, Masato; Nakazato, Yuji; Daida, Hiroyuki; Sakurai, Takashi; Morimoto, Sachio; Kurebayashi, Nagomi.

In: PloS one, Vol. 9, No. 7, e101838, 07.07.2014.

Research output: Contribution to journalArticle

Odagiri, F, Inoue, H, Sugihara, M, Suzuki, T, Murayama, T, Shioya, T, Konishi, M, Nakazato, Y, Daida, H, Sakurai, T, Morimoto, S & Kurebayashi, N 2014, 'Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice', PloS one, vol. 9, no. 7, e101838. https://doi.org/10.1371/journal.pone.0101838
Odagiri, Fuminori ; Inoue, Hana ; Sugihara, Masami ; Suzuki, Takeshi ; Murayama, Takashi ; Shioya, Takao ; Konishi, Masato ; Nakazato, Yuji ; Daida, Hiroyuki ; Sakurai, Takashi ; Morimoto, Sachio ; Kurebayashi, Nagomi. / Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice. In: PloS one. 2014 ; Vol. 9, No. 7.
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