Congestive heart failure (CHF) is a worldwide epidemic. It is estimated, for example, that in Europe around 10 million people are suffering from this disease. Despite some progress in medical treatment within the last 10 years, morbidity and mortality of CHF are still high: 70-80% of patients suffering from heart failure will die within the next 8 years. Heart failure develops mainly after myocardial infarction, chronic arterial hypertension, diseases of the cardiac valves (e.g. aortic valve stenosis), viral myocarditis or genetic disease. Associated with all these different disease entities is a profound alteration of the ventricular shape and function, which is triggered by cardiac overload as well as local and systemic activation of specific cytokines and growth factors. As a final common pathway of almost every heart disease leading to heart failure, the left cardiac ventricle dramatically dilates, while the left ventricular walls become increasingly thinner. This progressive dilation markedly increases wall stress, which in turn leads to further damage to the myocardium and diminishes the capability of the heart to pump blood into the circulation.
Our lab study the molecular mechanisms responsible for cardiac hypertrophy and remodeling during heart failure. Specifically we focus on the genome organization and the epigenetic modifications that control gene expression in the heart and on the mechanisms that differentially control concentric and eccentric cardiac growth in order to suggest additional targets for treating human disease.
Genome organization and gene expression in cardiac remodeling
Transcriptional regulation in mammals was simplistically viewed as a process in which soluble protein factors are recruited to promoters, located immediately 5′ of a protein encoding gene, to activate or repress transcription. However, more recent data suggest that the nucleus is an ordered three-dimensional organelle, in which theorganization of the genome appears to have implications for orchestrated gene expression. Data suggest that the expression of some genes correlates with their genomic environment. This environment consists of interactions of DNA loci with nuclear structural components such as the nuclear lamina and the nucleoporins and interaction of DNA loci with remote sequences on the same or other chromosomes.
The nuclear envelope is the main fixed structure of the nucleus, and has long been thought to provide anchoring sites for chromosomes, and thus to help organize the genome inside the nucleus. The nuclear envelope consists of a double lipid membrane punctured by nuclear pore complexes (NPCs), which act as channels for nuclear import and export. The nucleoplasmic surface of the inner nuclear membrane is coated by a sheet-like protein structure called the nuclear lamina. Interactions of the genome with the nuclear lamina have been mapped by means of DamID technology. This analysis suggested that the nuclear lamina is typically associated with large genomic domains containing predominantly inactive genes. We have used the DamID technique and studied the interactions of genomic loci with nucleoporins and showed that these associations can by modified by histone deacetylases 4 as a mechanism for controlling gene expression in cardiomyocytes.
Cardiomyocyte hypertrophy is mediated by the activation of a coordinated gene program. Recent data suggest that the organization of the genome has implications for orchestrated gene expression, and there is also evidence for spatial clustering of active genes in the nucleus. These observations suggest that cardiomyocyte hypertrophy would be accompanied by a coordinated shift in nuclear organization and genome-genome associations. We study how these mechanism operates and control cardiac structure and function.
Heart failure can be divided into different pathophysiological and functional categories. A key feature of congestive heart failure is the process of cardiac remodeling which may ultimately be detrimental to cardiac function. Characteristically, the cellular response tovolume overload is cardiomyocyte elongation – termed eccentric hypertrophy, whereas in response to pressure overload cardiomyocytes grow in width – concentric hypertrophy. Concentric hypertrophy, caused by addition of sarcomeres to myocytes in parallel, results in an increase in cardiac wall thickness and reduced chamber volume. Eccentric hypertrophy, caused by addition of sarcomeres in series, leads to a large, dilated ventricle with relative wall thinning.
Our data highlighted a signaling system which is involved in inducing one type of hypertrophy over the other (concentric vs. eccentric). These data identifies the MEK-ERK signaling cascade as an important pathways governing the type of hypertrophy that the cardiomyocyte is due to undergo. Activation of the kinase ERK was shown to be an inducer of concentric hypertrophy, and elimination of ERK in mice led to spontaneous eccentric hypertrophy.Our data also showed how modulating these signaling pathways leads to a phenotypical difference on the cellular level – elongated cardiomyocytes when eccentric hypertrophy was induced vs. wide cardiomyocytes in concentric hypertrophy.
Understanding the mechanism of asymmetric addition of sarcomeres to cardiomyocytes is therefore the fundamental basis for understanding pathological growth patterns in the heart.
Most aging individuals have progressively enlarging accumulation of calcium in their major arteries. These vascular calcifications, that appear in the walls of blood vessels such as the aorta, coronary, carotid and femoral arteries and in the leaflets of heart valves cause stiffness and impair hemodynamics resulting in hypertension and organ ischemia, valve stenosis, cardiac hypertrophy, and congestive heart failure. The presence of such calcification in any arterial wall is associated with a 3–4-fold higher risk for mortality and cardiovascular events. We are trying to elucidate the molecular mechanisms responsible for vascular and valve calcifications and find novel approaches to stop this devastating process.