The heart responds to stress and increased demand by mounting an adaptive or compensatory hypertrophic response to normalize cardiac output. With prolonged stress, this adaptive phase devolves to a maladaptive or decompensatory hypertrophy marked by the death of metabolically depleted cardiomyocytes and replacement by collagen-producing myofibroblasts that produce a scarring fibrosis. Of the processes underlying the progression to decompensatory hypertrophy, metabolic failure and scarring fibrosis are the most consequential making them key targets for therapeutic intervention. These processes are genetic in nature with well-defined genes and regulatory mechanisms controlling their expression. But exactly how hypertrophic stress signals interact with these regulatory mechanisms to control metabolic or fibrotic gene expression and how this allows the heart to adapt (or not) to stress has yet to be adequately defined. Without this knowledge, attempts to devise therapies to treat cardiac hypertrophy by either maintaining the adaptive or preventing the maladaptive response are likely to be unproductive. The long-term goal of our research is to understand the molecular mechanisms with which the heart translates hypertrophic stress signals into a genomic stress response. Our laboratory has been studying a molecule called CLP-1 (Cardiac Lineage Protein-1) that we have shown to be critical for integrating hypertrophic stress signals into a genomic stress response. CLP-1 is an inhibitory transcriptional modulator that controls the activity of P-TEFb (P-Transcriptional Elongation Factor b), a transcriptional regulator that activates RNA polymerase II to transcribe genes. As a critical regulator of gene transcription, CLP-1 plays an important role in a variety of physiologicl and pathological processes that involve integration of extracellular signals into a coordinated genomic response. The objective of this application is to determine how in response to hypertrophic stimuli CLP-1 controls the transcription of genes in the metabolic program regulating energy substrate usage and in the fibrotic program regulating remodeling of the hypertrophic ventricular myocardium. Our hypothesis is that reduced levels of the CLP-1 transcriptional inhibitor could be increasing the transcriptional competency and responsiveness of compensatory stress response genes, including metabolic genes, in order to maintain cardiomyocyte viability at levels that mitigate formation of the more damaging form of fibrosis, reparative or scarring fibrosis. Our experimental model for examining this hypothesis are mice with reduced CLP-1 gene dosage, CLP-1+/- heterozygous mice, rendered hypertrophic physically or by crossing with established mouse models of hypertrophy. To test our hypothesis, we propose three specific aims.
In aim #1, we will determine if the genes directing energy substrate usage are up-regulated to maintain the metabolic output and viability of hypertrophic cardiomyocytes.
In aim #2, we will examine the type of fibrosis that develops in CLP-1+/- hypertrophic hearts during the progression from compensatory to decompensatory hypertrophy to determine if reduced CLP-1 levels and sustained metabolic viability of hypertrophic cardiomyocytes mitigates formation of the more severe form of reparative or scarring fibrosis. And in aim #3, we will determine if the CLP-1-P-TEFb regulatory mechanism can directly up-regulate specific stress response genes by potentiating the signal transduction pathway controlling their expression. This approach is innovative in that it shifts the focus away from studies on the causes of heart disease to those focusing on how to prevent the diseased heart from progressing to failure. Since most people with heart disease fall into this latter category, they stand to benefit from the insights our research can provide. In all, our studies should demonstrate that CLP-1 occupies a critical position for controlling the response of cardiac cells to hypertrophic stimuli via its control of stress response genes. These studies are significant since they will provide greater insight into the molecular events underlying the adaptive hypertrophic response and how they can be controlled to mitigate the progression of hypertrophic hearts to contractile dysfunction and failure.
A recent Institute of Medicine study of aging veterans of the Vietnam War reports that individuals exposed to Agent Orange are increasingly suffering from hypertension and ischemic heart disease at a rate that is almost twofold greater than the general population. Since these conditions inevitably lead to heart failure and death, the only recourse left to afflicted individuls is to prevent the progression of these manageable heart diseases into end-stage heart failure. Our research proposal focuses on the molecular mechanisms driving cardiomyocytes from an adaptive, compensatory hypertrophy to a maladaptive, decompensatory one. By its very nature, this represents a shift away from a focus on how heart disease arises and might be prevented to one that focuses on how to treat the diseased heart and prevent its progression to failure. Since most people with heart disease fall into this latter category, they stand to benefit from the insights our research can provide on the molecular mechanisms driving the heart into pathological hypertrophy.
