Introduction Clinical trials have shown that carvedilol is highly effective against heart failure (HF). Carvedilol, unlike propranolol, has direct antioxidant effects and is capable of mitigating oxidative stress in HF patients. Moreover, it has been suggested that carvedilol has an indirect antioxidant mechanism that could involve the initial production of non-lethal levels of oxidative stress leading to the regulation of an uncharacterized antioxidant response that later counters oxidative stress.
Hypothesis We hypothesized that carvedilol's indirect antioxidant mechanism may involve the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch ECH associating protein 1 (Keap1) pathway, which is a major antioxidant pathway involved in cardiovascular, pulmonary, and neoplastic diseases.
Methods Using H9C2 rat myoblasts, we confirmed the activation of the Nrf2/Keap1 pathway by detecting levels of downstream protein targets hemeoxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO-1). We transfected H9C2 cells with reductive-oxidative green fluorescent protein (roGFP) fused with human glutaredoxin 1 that targeted mitochondria or cytosol. Redox state changes were quantified by normalized roGFP intensity ratios measured using live-cell imaging.
Results In the short term, carvedilol oxidized both cellular compartments while propranolol did not. In the long term, carvedilol upregulated the production of HO-1 and NQO-1 while propranolol downregulated these antioxidant proteins. These results demonstrate that carvedilol's indirect antioxidant effect involves the Nrf2/Keap 1 pathway. This has strong implications as carvedilol is a commonly used, highly effective beta-blocker and elucidating its antioxidant mechanisms can potentially expand the use of carvedilol for the treatment of other diseases, inform the development of new therapeutics, and optimize HF treatment.
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