The role of CaMKII-delta subtypes in myocardial ischemia/reperfusion injury
- Author(s): Gray, Charles Burdis Burns
- Advisor(s): Brown, Joan H
- et al.
Ca2+ dysregulation underlies many forms of cardiac stress and contributes significantly to arrhythmia and dysfunction during heart disease. Ca2+/CaM-dependent protein kinase II (CaMKII) is a multifunctional kinase that is activated by intracellular Ca2+, and signals through a variety of substrates to regulate cardiomyocyte biology. Elevated CaMKII activity has been associated with a range of pathologies including Ca2+ leak from the sarcoplasmic reticulum, mitochondrial dysfunction, and cell death. The predominant form of CaMKII in the heart is CaMKIIδ, which is alternatively spliced to yield the CaMKIIδB and CaMKIIδC subtypes. This dissertation describes the role of CaMKIIδ in cardiac stress generally, and specifically the role of the CaMKIIδB and CaMKIIδC subtypes in ischemia/reperfusion injury. Chapter 1 provides background information on the role of CaMKIIδ in cardiovascular disease and the structure and function of CaMKIIδB and CaMKIIδC. Chapter 2 describes the majority of the dissertation, focusing on studies on the subcellular distribution of CaMKIIδ subtypes and their role in ischemia/reperfusion injury and inflammatory signaling downstream of NF-κB. Chapter 3 contains studies on the involvement of CaMKIIδ in pathological signaling during cardiac stress elicited by chronic β-adrenergic stimulation and Gq overexpression. Chapter 4 describes ongoing and future studies and the relevance of these findings to human disease.