Insulin-mediated ROS/RNS signaling in cardiac myocytes

In Austria, a person dies every fifty minutes as a consequence of diabetes mellitus. First described in the 16th century, this metabolic disorder has been one of the most common prosperity diseases since the 1960s. Pathologically increased blood glucose levels interfere with many cell functions, causing faster aging and various secondary diseases. Diabetes is associated with multiple consecutive symptoms which cause high therapy costs, notably neurological disorders and cardiovascular diseases. People suffering from diabetes frequently develop typical pathologies, generally termed cardiomyopathy and featuring prominently among the most frequent causes of death. However, the molecular changes triggering these typical syndromes are largely unknown. In this research project conducted in cooperation with Prof. Thomas Michel of the Harvard Medical School in Boston (USA), we are investigating specific signal changes resulting in functional disorders in diabetic cardiomyopathy. To this end, we use sophisticated biosensors which we have recently developed in our laboratory. These novel probes and powerful microscopy techniques enable real-time imaging of reactive oxygen and nitrogen species in cardiac muscle cells. Radicals like hydrogen peroxide or nitric oxide are small molecules which, when in excess, can prove harmful. We assume that insulin, the very hormone whose blood-glucose-level-inhibiting function is impaired in diabetics, triggers excessive formation of such radicals in the diabetic heart, thus disrupting the physiological function of the myocardium. Insights gained from this research can lead to the development of improved therapeutic avenues.

Nitric oxide (NO) and hydrogen peroxide (H2O2) belong to the group of reactive oxygen species. It has been known for 40 years that NO is one of the most important messenger substances in our body because it regulates important functions in the cardiovascular system (e.g. blood pressure). However, hydrogen peroxide, which has a mild oxidative effect, has always been associated with aging processes and viewed as harmful because it destroys proteins and lipids and makes the skin look bad, at least that was believed. Today it is known that oxidative stress plays an important role in almost all cardiovascular and neurodegenerative diseases, albeit like a double-edged sword. Clinical meta-studies over the past few decades have shown that antioxidant therapies with vitamin C and vitamin E are more harmful (even fatal for heart failure) than helpful. Today we know that there is a connection between NO and hydrogen peroxide, but the mutual effect is not yet fully understood. In order to better examine these functions in cardiovascular cells, we have produced so-called chemogenetic tools that allow us to specifically trigger oxidative stress in cellular compartments and tissue-specific. In combination with genetically encoded biosensors, we can examine several parameters in real-time. These investigations have led to several groundbreaking results in the last few years, especially since we were able to describe the biochemical relationships in these free radicals for the first time in endothelial cells and, with the help of these chemogenetic tools, we were able to generate a new animal model system for heart failure model systems with the help of which we can determine the effect of various pharmaceuticals and investigate the role of oxidative stress. Our techniques and results are unexpected and have the potential for a paradigm shift in redox biochemistry and in the cardiovascular system.