We strive to decipher mechanisms of structural, functional, and electrical remodeling in heart disease with an eye toward therapeutic intervention.
Our studies are based largely on genetic and surgical models of cardiac hypertrophy and failure in animals.
It is widely agreed that derangements in intracellular Ca2+ homeostasis are proximal events in many types of heart disease. Further, some evidence implicates abnormal Ca2+ handling in the pathogenesis of disease progression, possibly participating in a vicious cycle with transcription and other processes.
Using biophysical, electrophysiological, and molecular methods, work is underway to explore this process as a potential target for therapeutic intervention.
We, and others, have hypothesized that cardiomyocyte death contributes to the transition from stable hypertrophy to heart failure. We have collected recent evidence implicating autophagy, a highly conserved pathway for recycling intracellular proteins and organelles, in the pressure-stressed heart. In other contexts, autophagy is capable of inducing a caspase-independent form of programmed cell death.
Work is underway to elucidate molecular mechanisms of autophagy in heart and to explore its contribution to the pathogenesis of heart failure.
Many types of heart disease present variably during the course of the 24-hour day. Within the cardiac myocyte, several hundred genes manifest significant diurnal variation in expression. Recent work in our lab has demonstrated that environmental stimuli are capable of "resetting" this cardiac clock, just as environmental stimulation (in the form of light) can reset the circadian pacemaker in the brain.
Work is underway to decipher the molecular basis of the environmental responsiveness of the cardiac clock.
DRAL (Down-regulated in Rhabdomyosarcoma LIM domain protein) is a molecule implicated in transcriptional control of multiple genes. Depending on context, DRAL functions as a transcriptional activator or repressor.
In DRAL knockout mice, cardiac growth in response to β-adrenergic stress is amplified, suggesting that DRAL functions to limit pathological remodeling.
Cardiac hypertrophy and failure are associated with substantial risk of malignant ventricular arrhythmia and consequent sudden cardiac death. Pathological prolongation of the ventricular action potential contributes importantly to the propensity to arrhythmia.
In a model of pressure-overload cardiac hypertrophy, we have found that increased expression and function of the cardiac L-type Ca2+ channel underlies this action potential prolongation.
Work is underway to decipher transcriptional control of channel expression, post-translational regulation of channel function, and apparent coupling of the channel with the transient-outward K+ channel.
Under conditions that promote muscle growth, there is coordinated activation of pro-growth mechanisms and suppression of anti-growth pathways.
Recent studies in skeletal muscle point to Forkhead (FOXO) proteins as critical governors of the balance between anabolic and catabolic responses, and work is underway in our lab to explore this in heart.
Recent evidence has implicated histone acetylation as a mechanism governing cardiac gene expression and pathological growth of the heart.
Working with a model of pressure-overload cardiac hypertrophy, we have found that suppression of histone deacetylases (HDACs) blunts hypertrophy.
Importantly, despite significant attenuation of hypertrophic growth, cardiac function and general health are preserved, suggesting that HDACs regulate a pathological type of hypertrophy.