Pathogenesis of Heart and Liver Diseases in Acquired and Genetic Iron-overload Disorders Resveratrol as potential therapy

  • Author / Creator
    Das,Subhash K.
  • Abnormal iron metabolism leads to cardiac and hepatic iron-overload disorders in an epidemic proportion. Irregular iron absorption results in iron deposition in different organs of the body including heart and liver. Iron-overload heart and liver diseases are commonly observed in patients with genetic hemochromatosis and secondary iron-overload, which are a common cause of end organ failure and mortality worldwide basis. An excess amount of iron associated with iron induced oxidative stress that leads to iron-overload cardiomyopathy and liver dysfunction respectively. We developed murine models of iron-overload with cardiomyopathy and liver disease to understand new insights into the pathogenesis and novel therapeutic effects of resveratrol. Cardiac and hepatic iron-overload pathogenesis showed dose-dependent iron-overload, oxidative stress, lipid peroxidation and fibrosis; however reduction in SERCA2a protein with defective calcium cycling without any inflammatory response is noticed in iron-overload hearts, which are key factors for the development of diastolic and systolic dysfunction. In contrast, hepatomegaly, hepatic inflammation, hepatic cell death and hepatic steatosis are well noticed in hepatic iron-overload. Resveratrol therapy improved cardiac function by decreasing iron-induced oxidative stress, myocardial lipid peroxidation, cardiac fibrosis, and hypertrophy; normalize calcium cycling defects by improving SERCA2a. In contrast resveratrol, therapy also improved liver function by reducing hepatic oxidative stress, lipid peroxidation, hepatic inflammation, hepatic cell death and hepatic steatosis. Consistent with the role of iron-induced myocardial oxidative stress in the development of heart disease, iron-overload female mice showed normal cardiac function with better survival rate without iron induced oxidative stress, highlighting the antioxidant properties of the female sex hormone estrogen. These results indicate that iron-induced oxidative stress is the key driver in the development of heart and liver diseases. There is no effective therapy available to prevent the global clinical burden of iron-overload, however, the mainstay therapies for iron-overload are phlebotomy and chelation therapy and these therapies have several limitations. Therefore, given the high degree of iron induced oxidative damage, we proposed that the pleiotropic effects of resveratrol represent a potential therapy to treat heart and liver diseases in iron-overloaded conditions.

  • Subjects / Keywords
  • Graduation date
    Fall 2016
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Specialization
    • Experimental Medicine
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Dr. Jason R.B. Dyck (Department of Pediatrics)
    • Dr. Sean Michael McMurtry (Department of Medicine)
    • Dr. Paul Fedak (University of Calgary) External examiner
    • Dr. Allen Murray (Department of Medicine)
    • Dr. Karen Madsen (Department of Medicine)