Phosphoinositide 3-Kinase (PI3K(p110α)) Directly Regulates Key Components of the Z-disc and Cardiac Structure

Abstract

Maintenance of cardiac structure and Z-disc signaling are key factors responsible for protecting the heart in a setting of stress, but how these processes are regulated is not well defined. We recently demonstrated that PI3K(p110␣) protects the heart against myocardial infarction. The aim of this study was to determine whether PI3K(p110␣) directly regulates components of the Z-disc and cardiac structure. To address this question, a unique three-dimensional virtual muscle model was applied to gene expression data from transgenic mice with increased or decreased PI3K(p110␣) activity under basal conditions (sham) and in a setting of myocardial infarction to display the location of structural proteins. Key findings from this analysis were then validated experimentally. The three-dimensional virtual muscle model visually highlighted reciprocally regulated transcripts associated with PI3K activation that encoded key components of the Z-disc and costamere, including melusin. Studies were performed to assess whether PI3K and melusin interact in the heart. Here, we identify a novel melusin-PI3K interaction that generates lipid kinase activity. The direct impact of PI3K(p110␣) on myocyte structure was assessed by treating neonatal rat ventricular myocytes with PI3K(p110␣) inhibitors and examining the myofiber morphology of hearts from PI3K transgenic mice. Results demonstrate that PI3K is critical for myofiber maturation and Z-disc alignment. In summary, PI3K regulates the expression of genes essential for cardiac structure and Z-disc signaling, interacts with melusin, and is critical for Z-disc alignment.An important question in cardiac biology is what makes one heart stronger, or more capable of resisting stress, than another. Maintenance of cardiac structure and Z-disc signaling are considered key factors responsible for protecting the heart in a setting of stress. Mutations of genes encoding proteins of the costamere and Z-disc have been linked with cardiomyopathies in animals and humans (1, 2). Costameres are specialized membrane junctions that physically connect the Z-disc to the basal lamina outside of the cell. The Z-disc is well recognized for its role in maintaining structural integrity and, more recently, has emerged as a "hot spot" or nodal hub of cardiomyocyte signaling, converting mechanical signals into chemical signals, leading to a transcriptional response and induction of a cardiac phenotype such as hypertrophy (1). Despite progress in this area, the mechanisms responsible for regulating components of the costamere and Z-disc are not well defined (2).The p110␣ isoform of phosphoinositide 3-kinase (PI3K-(p110␣)/PIK3CA) has cardioprotective properties (3). We recently demonstrated that cardiac expression of a constitutively active (ca) 3 PI3K transgene (increased PI3K activity) provided protection in a mouse model of myocardial infarction (MI), whereas a reduction in cardiac PI3K activity (utilizing a dominant negative (dn) PI3K transgene) accelerated the progression of heart failure (4). This makes target...

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