Clinical Pharmacology & Biopharmaceutics
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Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes leading to contractile
dysfunction and cardiac abnormalities, which increases cardiovascular diseases in the elderly. Inducible antioxidant pathways
are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are
impaired in the aging heart. Acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function
in young mice (~2 months), but aging mouse (>23 months) hearts exhibit significant oxidative stress and cardiac hypertrophy
due to impaired Nrf2 signaling. Under basal physiological conditions, disruption of Nrf2 showed minimal effects on antioxidant
defenses in young Nrf2-/- mice. Interestingly, mRNA and protein levels of antioxidants were dramatically (*p<0.001) decreased
in Nrf2-/- when compared to WT at 2 months of age, suggesting central regulation of defense mechanisms occurs through Nrf2.
Further analyses showed that the aged mice had a significant increase in ROS along with a decrease in glutathione (GSH) levels
and impaired antioxidants in Nrf2-/- when compared to WT. Disruption of Nrf2 appears to induce oxidative stress (increased
ROS, HNE-positive proteins), ubiquitination and pro-apoptotic signals in the heart of aging mice. Subsequent pharmacological
induction/activation of Nrf2 prevented the deleterious effects of oxidative stress and aging. Our findings conclude that though the
loss of Nrf2 is not amenable at younger age; it could severely affect the myocardial antioxidant defenses upon aging. Thus, Nrf2
signaling might be a potential therapeutic target to protect the heart from age-dependent accumulation of ROS by rescuing redox
homeostasis to prevent age-related cardiac disorders.
Namakkal S. Rajasekaran has completed his Ph.D. (Biochemistry) at the age of 28 years from the University of Madras and subsequent postdoctoral
studies from Indian Institute of Technology Madras (IITM) and the University of Utah School of Medicine/Cardiology. Presently, he is Assistant
Professor and the Director of Cardiac Aging & Redox Signaling Laboratory at the Department of Medicine, University of Utah, Salt Lake City, UT. He
has published more than 20 papers in reputed journals (including Cell, PNAS, Physiological Genomics, ARS, FRBM, PLoS Genetics, PLoS One,
Cardiovascular Research, BBA, AJP etc.) and serving as reviewer for multiple peer-reviewed journals. Dr. Rajasekaran has discovered the concept
of ?Reductive Stress (RS)? and its pathological role in protein aggregation cardiomyopathy, which had attracted several media news releases and
highlights in reputed journals. Recently, his lab has decoded the transcriptional mechanisms for RS and Dr. Rajasekaran has received R01 Research
Grant from the National Institute of Health to investigate the mechanisms for ?Reductive Stress and Proteotoxic Cardiac Disease?.
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