Pharmacology and toxicology

Various physiological functions such as smooth muscle cell relaxation and platelet aggregation are regulated by the mediators nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). To investigate the molecular mechanisms involved in NO/cGMP signaling and its regulation under physiological and pathophysiological condition we apply ex vivo tissues models (e.g., vasomotor function studies in organ baths, Langendorff perfusion of isolated hearts), cell culture models (e.g. endothelial cells, smooth muscle cells) as well as enzymatic assays with purified enzymes including NO synthase (NOS), soluble guanylyl cyclase (sGC), and aldehyde dehydrogenase II (Aldh2). The outcome of the research aims at contributing to a better understanding of the role of NO/cGMP as regulator of blood pressure and cardiac function in health and disease. In an expanded approach, NO/cGMP signaling in blood vessels and heart are investigated with a special focus placed on lipid and carbohydrate homeostasis.

Another research interest lies in studying the protective effects of adenosine signaling in the heart. Special emphasis is given to the role of adenosine kinase (ADK), which catalyzes the conversion of adenosine into adenosine monophosphate (AMP). Modulation of cardiac adenosine levels is achieved by pharmacological inhibition or genetic manipulations in mice. Studies are performed with isolated cardiomyocytes and mouse models. In this context, the link between adenosine metabolism and cardiac protein quality control is of special interest.

Nowadays, adipose tissue is no longer regarded as passive storage unit for excessive energy but rather represents a highly active endocrine organ that secretes vasoactive hormones and inflammatory cytokines. A research focus is to unravel the role of adipose tissue in the development of cardiovascular disease. Special emphasis is placed on perivascular adipose tissue inflammation. To this purpose, studies with cultivated fat cells, isolated tissues, and transgenic mouse models are performed. These studies should provide in depth insight into the adipose-vessel axis and may pave the way for the development of novel therapeutic strategies for metabolically-induced cardiovascular disorders.

Beyond their central role in hemostasis, platelets modulate immune responses by direct interaction with immune cells such as monocytes and neutrophils as well as by release of their granule content, which contains a plethora of molecules such as growth factor and inflammatory molecules. Platelets are sensitive sentinels that become activated in response to metabolic/inflammatory stimuli and contribute to the development of atherosclerosis, fatty liver disease and adipose tissue inflammation. Understanding the mechanisms of platelet activation and platelet-mediated immune responses under pathological conditions will help to employ the reveal the theragnostic potential of platelets.

Adipose tissue is more than just an organ important for energy storage. It plays a central role in maintaining metabolic homeostasis and acts as an endocrine organ. Dysfunctional adipose tissue is strongly associated with metabolic abnormalities such as dyslipidemia, insulin resistance, and glucose intolerance. The combination of these abnormalities, known as the metabolic syndrome, is a major contributor to morbidity/mortality from a variety of diseases including type 2 diabetes. Type 2 diabetes is mainly caused by lipid deposition in insulin-sensitive tissues (e.g. liver, skeletal muscle) and insulin-secreting beta cells. Thus, modification of adipose tissue-derived lipid metabolites has therapeutic potential, by reducing ectopic lipid accumulation and therefore improving peripheral insulin action, but also by directly providing signaling lipids for beta cell function. One major focus of our research is to investigate mechanisms by which adipose tissue-derived lipids contribute to the insulin secretory function of the pancreas to provide new insights into the pathophysiology of diabetes.

The research programs of the Ludwig Boltzmann Institute Arthritis and Rehabilitation (LBIAR) are addressing questions of clinical and translational research in the fields of rheumatology, balneology and rehabilitation. The focus of clinical research is on the two major rheumatic diseases, rheumatoid arthritis (RA) and osteoarthritis (OA), the focus of translational research is on cellular and molecular mechanisms of balneotherapy, especially sulphur spa, radon and nuclear magnetic resonance therapy. The major aim of the research group located at the Department of Pharmacology & Toxicology is to elucidate the underlying cellular and molecular mechanisms of H2S in vitro and in vivo. Therefore, the following questions will be addressed:

• Which cell types are responsive to exogenous H2S treatment?
• Which are the primary effects in inflammatory and degenerative processes?
• What are the underlying molecular mechanisms of H2S signaling?
• Development of novel H2S-releasing drugs for possible therapeutic application.