The significance and pathogenic consequences of proteotoxicity and proteinopathy in failing hearts have received recent clinical notice. Accumulation of defective proteins and their aggregation impair proteostasis and lead to pathological consequences in cardiomyocytes. A homeostatic balance (proteostasis) between synthesis and degradation of defective proteins is crucial for the dynamically active cardiomyocytes. Mounting evidence indicates that a majority of protein aggregation cardiomyopathies (PAC) caused by mutations in cytoskeletal proteins or chaperones involve pre-amyloid aggregates, oxidative stress, mitochondrial dysfunction and apoptotic death of cardiomyocytes. We now demonstrate that constitutive activation of nuclear erythroid-2 like factor-2 (Nrf2) signaling is a potential mechanism for Reductive Stress (RS) and PAC in these pathogenic processes. Our findings pinpoint RS as the metabolic insult responsible for pathogenesis in human cardiac disease. Our long-term goal is to investigate the molecular mechanisms for RS mediated proteotoxic cardiac disease and explore relevant therapeutic interventions. We hypothesize that abnormal increases in intracellular reducing power contributes to RS, which will cause proteotoxic cardiac remodeling and dysfunction through impaired protein quality control mechanisms. Accordingly, we propose the following aims: (1) To determine whether chronic reductive stress (CRS) is sufficient to cause cardiac hypertrophy and pathological remodeling, (2) To determine whether CRS impairs endoplasmic reticulum (ER) and ubiquitin- proteasome function to promote proteotoxicity and protein aggregation and (3) To determine whether preventing RS or preserving ER function rescues the CaNrf2-TG mice from proteotoxic cardiac remodeling and dysfunction. To study these aims, we have established mouse models for RS by constitutively activating Nrf2 (CaNrf2) in the heart [CaNrf2-TG or Keap1-/-:aMHC-Cre-TG (cardiomyocyte-specific constitutive activation of Nrf2 signaling)]. First, we will determine the effects of RS on cardiac function, structural remodeling and stress- induced cardiac hypertrophy in mice with trans-aortic constriction. Next, we will study the effect of RS on redox potential of ER and investigate the mechanisms associated with ER stress and unfolded protein response pathways in the CaNrf2-TG or Keap1-/-:aMHC-CreTG mice with proteotoxic cardiac disease. Then, we will use pharmacological approaches to prevent RS or ER stress to rescue the proteotoxic cardiac disease. Alternatively, we will use genetic approaches to knock down Nrf2 to prevent RS and resultant proteotoxicity. A team of scientists and physicians with relevant experience in cardiac physiology, cardiac imaging, free-radical chemistry, biochemistry, molecular biology and gene therapy will be involved in this project. The proposal also includes a strong plan for educating the next generation (undergraduates and postgraduates) with cutting-edge research. The overall outcome of this study will yield new knowledge on RS and proteotoxic effects in the heart, which will likely enhance therapeutic applications in human patients in the next 5-6 years.
Accumulation of defective proteins and their aggregation impairs the protein quality and induces pathological enlargement (hypertrophy) of cardiac cells, which results in cardiac failure. Reductive stress (abnormal increase in reducing compounds) leads to dysfunction of the endoplasmic reticulum (a cellular component crucial for the synthesis and folding of proteins) and proteotoxicity. In our laboratory, we have generated new animal models with heart-specific reductive stress, and using these exclusive mouse models, we will study the pathways for cardiac remodeling and this will open up new areas of research to understand cardiovascular diseases in humans.
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