Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2.
In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM.
Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, Sapporo, Japan;
Tatsuya
T
Sato
Takeshi
T
Kobayashi
Atsushi
A
Kuno
Takayuki
T
Miki
Masaya
M
Tanno
Hidemichi
H
Kouzu
Takahito
T
Itoh
Satoko
S
Ishikawa
Takashi
T
Kojima
Tetsuji
T
Miura
Noritsugu
N
Tohse
D000200:Action Potentials; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D004562:Electrocardiography; D018398:Homeodomain Proteins / Q000378:metabolism; D007700:Kinetics; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D051665:Kv1.4 Potassium Channel / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D051672:Shal Potassium Channels / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism
D001786:Blood Glucose; D020746:Calcium Channels, L-Type; D018398:Homeodomain Proteins; C539715:Irx5 protein, rat; C496979:Kcna4 protein, rat; C497020:Kcnd2 protein, rat; C496758:Kcnip2 protein, rat; D051605:Kv Channel-Interacting Proteins; D051665:Kv1.4 Potassium Channel; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D014157:Transcription Factors; D011188:Potassium
Iroquois homeobox 5; Kv4.2; cardiac ion channel remodeling; type 2 diabetes; voltage-gated K+ channel-interacting protein 2