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Articles by I Kodama
Total Records ( 2 ) for I Kodama
  K Hidaka , M Shirai , J. K Lee , T Wakayama , I Kodama , M. D Schneider and T. Morisaki
 

Rationale: The paucity of specific surface markers for cardiomyocytes and their progenitors has impeded the development of embryonic or pluripotent stem cell–based transplantation therapy. Identification of relevant surface markers may also enhance our understanding of the mechanisms underlying differentiation.

Objective: Here, we show that cellular prion protein (PrP) serves as an effective surface marker for isolating nascent cardiomyocytes as well as cardiomyogenic progenitors.

Methods and Results: Embryonic stem (or embryo-derived) cells were analyzed using flow cytometry to detect surface expression of PrP and intracellular myosin heavy chain (Myhc) proteins. Sorted cells were then analyzed for their differentiation potential.

Conclusions: PrP+ cells from beating embryoid bodies (EBs) frequently included nascent Myhc+ cardiomyocytes. Cultured PrP+ cells further differentiated, giving rise to cardiac troponin I+ definitive cardiomyocytes with either an atrial or a ventricular identity. These cells were electrophysiologically functional and able to survive in vivo after transplantation. Combining PrP with a second marker, platelet-derived growth factor receptor (PDGFR), enabled us to identify an earlier cardiomyogenic population from prebeating EBs, the PrP+PDGFR+ (PRa) cells. The Myhc PRa cells expressed cardiac transcription factors, such as Nkx2.5, T-box transcription factor 5, and Isl1 (islet LIM homeobox 1), although they were not completely committed. In mouse embryos, PRa cells in cardiac crescent at the 1 to 2 somite stage were Myhc+, whereas they were Myhc at headfold stages. PRa cells clonally expanded in methlycellulose cultures. Furthermore, single Myhc PRa cell–derived colonies contained both cardiac and smooth muscle cells. Thus, PrP demarcates a population of bipotential cardiomyogenic progenitor cells that can differentiate into cardiac or smooth muscle cells.

  X Qi , Y. H Yeh , D Chartier , L Xiao , Y Tsuji , B. J.J.M Brundel , I Kodama and S. Nattel
 

Background— Sustained bradycardia is associated with long-QT syndrome in human beings and causes spontaneous torsades de pointes in rabbits with chronic atrioventricular block (CAVB), at least partly by downregulating delayed-rectifier K+-current to cause action potential (AP) prolongation. We addressed the importance of altered Ca2+ handling, studying underlying mechanisms and consequences.

Methods and Results— We measured ventricular cardiomyocyte [Ca2+]i (Indo1-AM), L-type Ca2+-current (ICaL) and APs (whole-cell perforated-patch), and Ca2+-handling protein expression (immunoblot). CAVB increased AP duration, cell shortening, systolic [Ca2+]i transients, and caffeine-induced [Ca2+]i release, and CAVB cells showed spontaneous early afterdepolarizations (EADs). ICaL density was unaffected by CAVB, but inactivation was shifted to more positive voltages, increasing the activation-inactivation overlap zone for ICaL window current. Ca2+-calmodulin–dependent protein kinase-II (CaMKII) autophosphorylation was enhanced in CAVB, indicating CaMKII activation. CAVB also enhanced CaMKII-dependent phospholamban-phosphorylation and accelerated [Ca2+]i-transient decay, consistent with phosphorylation-induced reductions in phospholamban inhibition of sarcoplasmic reticulum (SR) Ca2+-ATPase as a contributor to enhanced SR Ca2+ loading. The CaMKII-inhibitor KN93 reversed CAVB-induced changes in caffeine-releasable [Ca2+]i and ICaL inactivation voltage and suppressed CAVB-induced EADs. Similarly, the calmodulin inhibitor W7 suppressed CAVB-induced ICaL inactivation voltage shifts and EADs, and a specific CaMKII inhibitory peptide prevented ICaL inactivation voltage shifts. The SR Ca2+-uptake inhibitor thapsigargin and the SR Ca2+ release inhibitor ryanodine also suppressed CAVB-induced EADs, consistent with an important role for SR Ca2+ loading and release in arrhythmogenesis. AP-duration changes reached a maximum after 1 week of bradypacing, but peak alterations in CaMKII and [Ca2+]i required 2 weeks, paralleling the EAD time course.

Conclusions— CAVB-induced remodeling enhances [Ca2+]i load and activates the Ca2+-calmodulin-CaMKII system, producing [Ca2+]i-handling abnormalities that contribute importantly to CAVB-induced arrhythmogenic afterdepolarizations.

 
 
 
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