Date of Degree
PhD (Doctor of Philosophy)
Molecular Physiology and Biophysics
Mark E. Anderson
The multifunctional calcium and calmodulin dependent protein kinase II (CaMKII) is implicated in both animal models and human forms of cardiovascular disease. CaMKII is activated by elevated neurohormonal signals including enhanced â-adrenergic stimulation and angiotensin II signaling, whereas CaMKII inhibition is cardioprotective from these pathologic triggers. In addition to â-blockers and angiotensin II inhibitors, aldosterone antagonist drugs are the third and most recent class of pharmacologic agents comprising the frontline therapy for heart disease patients. Here, I show that CaMKII activation is important for cardiac aldosterone signaling in the post-myocardial infarction (MI) mouse model. Aldosterone infusion to MI mice increases cardiac rupture, a lethal and nearly untreatable clinical problem. CaMKII inhibition protects from aldosterone enhanced post-MI rupture. We previously reported microarray analysis of genes upregulated after MI but downregulated in the presence of cardiac CaMKII inhibition. Surprisingly, a number of these genes are involved in extracellular matrix remodeling. Here, I validated the microarray findings for matrix metalloproteinase 9 (MMP9), an extracellular matrix remodeling enzyme known to contribute to the rupture phenotype. My results support a sequence where aldosterone infusion after MI recruits NADPH oxidase-derived reactive oxygen species to enhance CaMKII oxidation and subsequent myocyte enhancer factor 2 driven increases in MMP9 expression in myocytes. I found that oxidative activation of CaMKII is critical for this rupture phenotype through a new transgenic mouse model that overexpresses methionine sulfoxide reductase A, which modulates CaMKII oxidation and therefore activation. These results implicate CaMKII activation in cardiac aldosterone signaling and reinforce the importance of CaMKII hyperactivity in acute cardiac remodeling after MI. Overall, this work supports myocardial CaMKII as a novel mediator of cardiac aldosterone stimulation of post-MI matrix remodeling and suggests potential efficacy for molecularly targeted anti-oxidant therapy in the treatment of patients after acute MI.
xiii, 115 pages
Includes bibliographical references (pages 97-115).
Copyright 2012 Beixin Julie He