Cardiovascular disease is the predominant cause of death and a major cause of disability in the developed world. An estimated 700,000 people die from cardiovascular disease each year in the United States. Regardless of insult, the heart undergoes a similar sequence of pathological remodeling events that progress from cellular hypertrophy to apoptosis and fibrosis, culminating in mechanical dysfunction, electrical instability, and end-stage heart failure. Here, we focus on cardiac hypertrophy, a critical maladaptive initiation event leading to pathological remodeling. The mineralocorticoid aldosterone (Aldo) is centrally involved in cardiac pathology. Aldo antagonist drugs are emerging as first line heart failure therapy with two independent clinical trials showing significant reduction in morbidity and mortality. Recent findings suggest Aldo exerts a direct action in cardiac tissue and induces myocardial hypertrophy. Recently, we reported a novel activation mechanism for calcium/calmodulin-dependent protein kinase II (CaMKII) through direct redox modification. CaMKII activation occurs via oxidation of critical methionine residues within its autoregulatory domain by reactive oxygen species (ROS). Since Aldo increases ROS, it may activate CaMKII. Our preliminary data strongly support the novel hypothesis that Aldo-induced myocardial hypertrophy works through CaMKII activation. Understanding the molecular pathway(s) underlying Aldo- induced cardiac pathology will give insight into the current benefits of Aldo blockade and will suggest novel therapeutic targets, in accordance with Goal 1 of the Strategic Plan for the National Heart, Lung, and Blood Institute. Focus is placed on the following aims: (1) Determine the role of CaMKII in Aldo-induced myocardial hypertrophy with in vitro myocyte culture system and in vivo CaMKII inhibition mice models. (2) Determine the molecular mechanism(s) of CaMKII activation by Aldo by using fluorescence and confocal microscopy to measure Aldo-induced ROS and CaMKIIoxidation. (3) Determine the role of methionine sulfoxide reductase A (MsrA) in reversing CaMKII activation and myocardial hypertrophy by Aldo, utilizing adenoviral transduction of MsrA in myocyte culture system. Lay Summary: Heart disease is the leading cause of death and disability in the United States. Aldosterone is a steroid hormone that is elevated in heart failure patients. This research proposal will investigate how aldosterone works inside the cell and may unveil new therapeutic targets to treat heart disease.
| He, B Julie; Joiner, Mei-Ling A; Singh, Madhu V et al. (2011) Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat Med 17:1610-8 |
