Arterial stiffening as a common pathophysiological mechanism in cardiac and kidney failure and brain degeneration.

The elasticity of the arterial wall is a physiologically elegant solution of nature for smoothing the pulsatile flow of blood from the heart to peripheral tissues. The loss of this elasticity during life is a consequence of pathophysiological alterations in the vessels eventually causing arterial stiffening. Emerging evidence demonstrates that arterial stiffness is an important driving force for multiple heart, kidney and brain pathologies (end-organ damage). Nevertheless, it is currently not clear which molecular pathways contribute to arterial stiffness and whether similar mechanisms link diverse end-organ pathologies. Therefore, the present proposal aims to investigate the following research questions in three work packages: Work package 1: Pathophysiological characterization of two mouse models of arterial stiffening and its relationship with end-organ damage. In this part of the project, we will characterize mouse models of two pathophysiological processes leading to arterial stiffness: endothelial dysfunction and extracellular matrix modification/calcification. Two appropriate mouse models, i.e. eNOS knockout mice and warfarin exposed mice will be examined in a longitudinal manner to investigate the time-dependent development of arterial stiffness and its relationship with end-organ damage (heart and kidney damage and brain degeneration). In a next step, a combined mouse model of arterial stiffness and cerebral beta-amyloid accumulation (cross breeding of one of the above models with APP23 transgenic mice) will be applied to explore whether arterial stiffness is able to enhance beta-amyloid accumulation in the brain, thereby promoting the development/progression of Alzheimer's disease. Techniques that will be used to measure arterial stiffness and end-organ damage include high-frequency ultrasound (Vevo2100), tonometry, pressure myography, immunohistochemistry and behavioral assessment of learning and cognition. Work package 2: What are the age-related molecular mechanisms that underlie arterial stiffness leading to end-organ damage? The second part of the project aims to unravel the (common) molecular pathway(s) that underlie the development of arterial stiffness and the end-organ damage by comparing protein expression/post-translational modification status in arteries, hearts, kidneys and brains originating from mice with and without arterial stiffening, using mass spectrometric isobaric mass-tag labeling proteomics (iTRAQ). We aim to investigate the age-dependent generation of potentially convergent pathological signaling processes, across the lifespan of mice, in stiffening arteries, damaged heart and kidney tissue and degenerating brain tissues. The search for potential common molecular pathway(s) ('disease signatures') underlying the development of arterial stiffness may allow the identification of new targets for the prevention or treatment of arterial stiffness and ensuing end-organ damage. Work package 3: How can arterial stiffness and subsequent end-organ damage be prevented or treated? The last work package will evaluate the efficacy of substances that potentially prevent or treat the development of arterial stiffness and the resulting end-organ damage, more in particular heart and kidney failure as well as beta-amyloid accumulation in the brain. Substances that will be tested include molecules that modulate new targets that were identified during the protein expression studies (WP2), affect endothelial dysfunction (NO-donor or guanylate cyclase activator), inhibit calcification (pyrophosphate) or stimulate autophagy (mTOR inhibitor). Taken together, this project aims to unravel the molecular processes involved in arterial stiffness that might lead to prevention and/or treatment of arterial stiffness and hence reduce the risk and severity of age-related heart and kidney damage and brain degeneration.

Keywords:KIDNEY DISEASE, ARTERIAL STIFFNESS, HEART FAILURE, BRAIN DISEASE

Disciplines:Cardiac and vascular medicine, Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences