Abstract
Cu(II)ATSM was developed as a hypoxia sensitive positron emission tomography agent. Recent reports have highlighted the neuroprotective properties of Cu(II)ATSM, yet there are no reports that it confers cardioprotection. We demonstrate that Cu(II)ATSM activates the redox-sensitive transcription factor Nrf2 in human coronary artery smooth muscle cells (HCASMC) and cardiac myocytes (HCM), leading to upregulation of antioxidant defense enzymes. Oral delivery of Cu(II)ATSM in mice induced expression of the Nrf2-regulated enzymes in the heart and aorta. In HCASMC, Cu(II)ATSM increased expression of the Nrf2 stabilizer DJ-1, and knockdown of Nrf2 or DJ-1 attenuated Cu(II)ATSM-mediated heme oxygenase-1 and NADPH quinone oxidoreductase-1 induction. Pre-treatment of HCASMC with Cu(II)ATSM protected against the pro-oxidant effects of angiotensin II (Ang II) by attenuating superoxide generation, apoptosis, proliferation and increases in intracellular calcium. Notably, Cu(II)ATSM-mediated protection against Ang II-induced HCASMC apoptosis was diminished by Nrf2 knockdown. Acute treatment with Cu(II)ATSM enhanced the association of DJ-1 with superoxide dismutase-1 (SOD1), paralleled by significant increases in intracellular Cu(II) levels and SOD1 activity. We describe a novel mechanism by which Cu(II)ATSM induces Nrf2-regulated antioxidant enzymes and protects against Ang II-mediated HCASMC dysfunction via activation of the Nrf2/DJ-1 axis. Cu(II)ATSM may provide a therapeutic strategy for cardioprotection via upregulation of antioxidant defenses.
Highlights
Reactive oxygen species (ROS) are important mediators of signaling in the cardiovascular system which are generated by endothelial and smooth muscle cells (SMC) and cardiomyocytes
There are no reports on the potential of Cu(II)ATSM to enhance the expression and activity of endogenous antioxidant defense enzymes regulated by NF-E2 related factor 2 (Nrf2)/DJ-1 signalling in the cardiovascular system
We have investigated for the first time whether treatment of human coronary artery SMC (HCASMC) and cardiomyocytes (HCM) with Cu(II)ATSM induces expression of antioxidant enzymes via activation of Nrf[2] and its co-activator protein DJ-1, thereby providing protection against the pro-oxidant effects of angiotensin II (Ang II), including SMC apoptosis, proliferation and increased intracellular calcium[16,17,18,19]
Summary
Reactive oxygen species (ROS) are important mediators of signaling in the cardiovascular system which are generated by endothelial and smooth muscle cells (SMC) and cardiomyocytes. There are no reports on the potential of Cu(II)ATSM to enhance the expression and activity of endogenous antioxidant defense enzymes regulated by Nrf2/DJ-1 signalling in the cardiovascular system. We have investigated for the first time whether treatment of human coronary artery SMC (HCASMC) and cardiomyocytes (HCM) with Cu(II)ATSM induces expression of antioxidant enzymes via activation of Nrf[2] and its co-activator protein DJ-1, thereby providing protection against the pro-oxidant effects of Ang II, including SMC apoptosis, proliferation and increased intracellular calcium[16,17,18,19]. By enhancing the association of DJ-1 with SOD1 and increasing SOD1 activity, Cu(II)ATSM may confer cardiovascular protection through activation of antioxidant defenses mediated by the Nrf2/DJ-1 axis
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