Cardiomyopathy and heart failure are characterized by transcriptional reprogramming of gene expression with activation of fetal genes, which correlate with cardiac performance and clinical outcome. Myosin heavy chain (MHC), which hydrolyzes ATP to drive muscle contraction, is the molecular motor in heart muscle cells. Two isoforms of MHC, α- and β-MHC, are present in mammalian hearts. The β-MHC has higher ATPase activity than β-MHC, and their relative amount in the heart changes under different pathophysiological conditions. Adult cardiomyocytes in mice are post-mitotic and express mainly α-myosin heavy chain (��α-MHC, also known as Myh6), whereas fetal cardiomyocytes are highly proliferative and express primarily �猀]-MHC (also known as Myh7). Adult hearts under pathological stress such as pressure overload, volume overload, ischemia or infarction develop cardiac hypertrophy, accompanied by a switch from α-MHC to fetal β-MHC, representing a return to the fetal state of cardiac differentiation. This eventually leads to contractile dysfunction and heart failure. The α- and β-MHC ratio correlates strongly with the overall cardiac performance in animals as well as in patients with cardiomyopathy and heart failure. Hearts expressing higher α-MHC have better clinical outcome under stress conditions than those expressing mainly β-MHC. Thus, strategies to control MHC expression represent attractive approaches for heart failure therapy.
Mechanisms bridging the developmental and pathological gene expression are not well understood. An important mechanism regulating gene expression involves modification of the chromatin, the higher-order structure in which DNA is packaged. Recent studies have greatly expanded our understanding of cardiovascular development and pathophysiology at the chromatin level, including chromatin remodeling and histone modification. A major chromatin-remodeling protein complex in vertebrates is the Brg1/Brm-associated-factor (BAF) complex, consisting of 12 protein subunits that utilize the energy derived from ATP hydrolysis to regulate nucleosome positioning. Brg1, the essential ATPase subunit of the BAF complex, plays critical roles in regulating gene expression, tissue growth and differentiation in fetal hearts and adult hearts under stress. In the fetal heart, Brg1 promotes cardiomyocyte proliferation by maintaining Bmp10 (bone morphogenic protein) expressionand suppressing a cell cycle inhibitor, p57kip2. In parallel, Brg1 preserves fetal cardiac differentiation by interacting with two classes of chromatin regulators- histone deacetylase (HDAC) and poly (ADP ribose) polymerase (PARP)- to repress β-MHC and activate β-MHC expression. In adults, Brg1 is turned off in cardiomyocytes. However, it is reactivated by cardiac stress and complexes with its embryonic partners, HDACs and PARP1, to induce a pathological switch from α- to β-MHC. Preventing such Brg1 re-expression decreases cardiac hypertrophy, abolishes fibrosis, reverses MHC switch, and thwarts heart failure. Our studies show that Brg1/BAF maintains cardiomyocytes in a fetal state of proliferation and differentiation, and demonstrate an epigenetic mechanism by which three classes of chromatin-regulating factors, Brg1/BAF, HDACs and PARP, cooperate to control developmental and pathological gene expressions. Importantly, BRG1 is also activated in the hearts of patients with hypertrophic cardiomyopathy. Its level of expression correlates strongly with the disease severity and MHC changes, suggesting a causal role of BRG1 in human hypertrophic heart disease.
???
Brg1/BAF may have regenerative and therapeutic implications given its newly identified roles in both fetal and adult cardiomyocytes. The stress-dependent activation of a developmental complex to modify chromatin structure in adult hearts provides a molecular and epigenetic explanation for fetal gene activation in the diseased adult myocardium. HDAC, PARP and Brg1/BAF are the major classes of epigenetic factors known to regulate cardiac myopathy. The induction of Brg1 and its associated chromatin complex by hypertrophic stimuli suggests that chromatin may ultimately be where all the stress-response signals converge for the regulation of MHC and other myopathic genes, a critical step toward the development of cardiomyopathy and heart failure. |
