Cardiac diseases: arrhythmias and heart failure
Cardiac diseases are among the leading causes of death worldwide. Ca2+ is a key player in both physiological and pathological processes in the heart. During normal excitation-contraction coupling, Ca2+ enters the cardiac myocyte during an action potential through voltage-dependent L-type Ca2+ channels in the sarcolemma. This Ca2+ entry triggers a huge release of Ca2+ from the sarcoplasmic reticulum via ryanodine receptor (RyR) Ca2+ release channels, a process termed Ca2+-induced Ca2+ release. Ultimately, this increase in cytoplasmic Ca2+ causes Ca2+ binding to the myofilaments and activation of contraction. The strength of contraction is regulated by the amount of Ca2+ released from the SR. Increased SR Ca2+ release causes augmented contraction, whereas decreased SR Ca2+ release results in reduced contraction of the cardiomyocyte. Disturbances of this highly regulated process may lead to cardiac disease including arrhythmias and heart failure, which are among the most serious and widespread cardiac diseases. A number of cardioactive peptides is involved in the regulation of cardiac Ca2+ homeostasis and may either aggravate or improve cardiomyocyte function in cardiac disease.
The research interest of our group is focused on the following topics:
1) Cytoplasmic Ca2+ signaling and arrhythmias
Systolic SR Ca2+ release is essential for contraction of the myocyte. Diastolic SR Ca2+ release, on the other hand, is detrimental. It activates the sarcolemmal electrogenic Na+/Ca2+ exchanger resulting in depolarization of the resting membrane potential (delayed afterdepolarizations), which in turn may trigger arrhythmias. In the normal heart, diastolic SR Ca2+ release is a rare event. In the stressed or diseased heart, however, diastolic SR Ca2+ release may increase and thus enhance the propensity for arrhythmias. Increased diastolic SR Ca2+ release has been found in atrial myocytes from patients with atrial fibrillation, the most common cardiac arrhythmia, as well as in ventricular myocytes in heart failure, where it is thought to trigger the fatal arrhythmias associated with the disease. Pharmacological agents normalizing aberrant diastolic SR Ca2+ release in cardiac diseases associated with arrhythmias are currently being tested for their potential use as novel anti-arrhythmic drugs.
2) Nucleoplasmic Ca2+ signaling and excitation-transcription coupling
Nucleoplasmic Ca2+ regulation in cardiac myocytes has gained much less attention than cytoplasmic Ca2+ regulation. Recent evidence, however, indicates that localized nucleoplasmic Ca2+ increases may specifically alter transcription via Ca2+-dependent enzymes (e.g. nuclear Ca2+/calmodulin-dependent protein kinase II). The link between electrical and/or pharmacological stimulation of the cardiac myocyte, nucleoplasmic Ca2+, and transcription is termed excitation-transcription coupling. Altered excitation-transcription coupling may be involved in the remodeling processes occurring during initiation and progression of cardiac diseases, including atrial fibrillation and heart failure. A better understanding of nucleoplasmic Ca2+ regulation thus holds the promise for the development of novel treatment strategies against cardiac diseases associated with remodeling.
3) Cardioactive peptides: angiotensin II, endothelin-1, and urocortin II
Cardioactive peptides are involved in a variety of physiological and pathophysiological processes including arrhythmogenesis and the development and progression of hypertrophy and heart failure. They are major drug targets in cardiovascular disease. Inhibition of the angiotensin system by either ACE inhibitors or AT1 receptor blockers is used for the treatment of hypertension and heart failure, whereas the endothelin receptor blocker bosentan is used for the treatment of pulmonary hypertension.
Urocortins (including urocortin II) represent a family of peptides involved in cardiovascular homeostasis. They exert pronounced effects on cardiac myocytes as well as on coronary and peripheral vessels. Although beneficial in animal models of heart failure, the cellular actions of urocortins on cardiac myocytes are only incompletely understood. A better understanding of the specific actions of urocortins on cardiac myocytes in health and disease, however, is a pre-requisite for their potential therapeutic use in heart failure.