Vascular dysfunction and oxidative stress in primary amyloidosis

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DESCRIPTION (provided by applicant): Primary systemic amyloidosis is a plasma cell dyscrasia that is often fatal especially if there is cardiac involvement. Untreated, patients with heart failure have median survival of 4-8 months, yet these patients are often ineligible for life-saving high dose chemotherapy and autologous stem cell transplantation. It results from the deposition of misfolded amyloid proteins derived from immunoglobulin light chains and affects the heart, gut, kidneys and peripheral nerves. Biopsy studies and animal studies suggest that amyloid light chains cause oxidative stress leading to tissue damage or dysfunction in colon and cardiac tissues. There is evidence that early endothelial dysfunction precedes onset of amyloid deposition and that amyloid light chains may cause acute tissue injury. Diffuse vascular dysfunction involving small and medium sized arteries may play a central role in causing multiorgan injury. Despite the grim prognosis associated with the disease, however, we know little about the mechanism of injury. Our preliminary results demonstrate impaired endothelial function in human adipose arterioles obtained from non-amyloid subjects following brief exposure to amyloid light chains. This was associated with increased superoxide production. Mitochondria targeted antioxidant treatment preserved endothelial function. We will expand on our initial observations. We plan to test our overall hypothesis that primary amyloid light chains acutely impair endothelial function by increasing reactive oxygen species production in both coronary arterioles and adipose arterioles from subjects without amyloid disease. We further hypothesize that the mitochondria is a source of reactive oxygen species and that antioxidant treatment with mitoquinone, a mitochondria targeted antioxidant will preserve endothelial function. To test these hypotheses, we propose to 1. measure endothelium-dependent and endothelium-independent dilation in isolated human coronary and adipose arterioles (from non-amyloid subjects) before and following exposure to amyloid light chains (obtained from primary amyloidosis subjects); 2. measure reactive oxygen species (superoxide and hydrogen peroxide) in coronary and adipose arterioles following exposure to amyloid light chain and 3. measure the effect of mitoquinone on endothelial function and reactive oxygen species generation in coronary and adipose arterioles following exposure to amyloid light chains. The proposal is novel and significant. It addresses for the first time the mechanism behind vascular injury and endothelial dysfunction in primary amyloidosis. We propose using a human tissue model for the first time in studying this disease that will have more relevant translational application as compared to animal or cell culture studies. We will also test a novel (mitoquinone) antioxidant therapy that may broaden management options for this fatal disease. Understanding the mechanism behind this early injury may allow us to discover new therapeutic strategies to address extensive organ damage in full-blown disease, a model that is seen in other vascular insults such as hyperglycemia, hypertension and hyperlipidemia. The information gathered and the application of the human vascular model may be useful in the study of other amyloid diseases that share common mechanisms of injury, such as Alzheimer's disease or diabetes. PUBLIC HEALTH RELEVANCE: Primary systemic amyloidosis can be a fatal disease and it is caused by the production and deposition of abnormal immunoglobulin light chain proteins in various organs such as the heart, blood vessels, kidneys, gut and liver. The cause of injury to blood vessels by amyloid light chains is unknown. The project will determine if exposure of isolated human blood vessels from discarded tissue to amyloid light chains will impair its function and whether this impairment is caused by oxidative stress. The project will also determine if mitoquinone, a novel antioxidant, will reduce the impairment in function of the blood vessel caused by amyloid light chains. The research will provide important information on the basis and possible treatment of primary systemic amyloidosis that may lead to improvement in survival in these patients.