Skip to Main Content
 

Global Search Box

 
 
 
 

Files

File List


Master's Thesis - Taylor Howard.pdf (1.76 MB)

ETD Abstract Container

Abstract Header

Investigating the mechanism underlying CaMKII-induced arrhythmias in ischemia using optical mapping

Howard, Taylor
http://rave.ohiolink.edu/etdc/view?acc_num=osu1523297730669223

Abstract Details

2018, Master of Science, Ohio State University, Biomedical Engineering.
The mechanisms underlying CaMKII-induced arrhythmias in ischemia/reperfusion (I/R) are not fully understood. My thesis research tested the hypothesis that CaMKII increases late Na+ current (INa,L) via phosphorylation of Nav1.5 at Ser571 during I/R, thereby increasing arrhythmia susceptibility. Action potential duration (APD) and arrhythmic events were measured by optical mapping in isolated, Langendorff-perfused mouse hearts during global ischemia and reperfusion. To provide mechanistic information on the role of CaMKII-dependent phosphorylation of Nav1.5 in arrhythmia, Scn5a knockin mice expressing Nav1.5 with constitutive phosphorylation [Nav1.5-Ser571Glut (S571E)] or ablation [Nav1.5-Ser571Ala (S571A)] of the CaMKII site at Ser571 were used. Wildtype (WT) hearts showed a significant increase in the levels of phosphorylated CaMKII and Nav1.5 at Ser 571 [(p-Nav1.5(S571)] following 15 minutes of ischemia (just before onset of reperfusion). Optical mapping studies revealed a significant prolongation of APD, increased recovery time, and increased arrhythmia susceptibility during I/R in S571E and WT mice compared to S571A mice. Pretreatment of hearts with Na+ channel blocker mexiletine (10 uM) increased recovery of APD and reduced arrhythmia susceptibility in WT mice during I/R. We conclude that CaMKII-dependent phosphorylation of Nav1.5 is a crucial driver for increased INa,L, arrhythmia susceptibility during I/R. Selective targeting of this CaMKII-dependent pathway may have therapeutic potential for reducing arrhythmias in the setting of I/R.
Tom Hund, Dr. (Advisor)
Sakima Smith, Dr. (Committee Member)
67 p.
Biomedical Engineering
CaMKII; ischemia reperfusion; late sodium current; optical mapping; arrhythmia

Recommended Citations

Citations

  • Howard, T. (2018). Investigating the mechanism underlying CaMKII-induced arrhythmias in ischemia using optical mapping [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523297730669223

    APA Style (7th edition)

  • Howard, Taylor. Investigating the mechanism underlying CaMKII-induced arrhythmias in ischemia using optical mapping. 2018. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1523297730669223.

    MLA Style (8th edition)

  • Howard, Taylor. "Investigating the mechanism underlying CaMKII-induced arrhythmias in ischemia using optical mapping." Master's thesis, Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1523297730669223

    Chicago Manual of Style (17th edition)

osu1523297730669223
206
© 2018, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.