Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

TY - JOUR

T1 - Cardioprotective effects of Cu(II)ATSM in human vascular smooth muscle cells and cardiomyocytes mediated by Nrf2 and DJ-1

AU - Srivastava, Salil

AU - Blower, Philip J.

AU - Aubdool, Aisah A.

AU - Hider, Robert C.

AU - Mann, Giovanni E.

AU - Siow, Richard C.

PY - 2016

Y1 - 2016

N2 - 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 induction. Pre-treatment of HCASMC with Cu(II)ATSM protected against the prooxidant 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 silencing. 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

AB - 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 induction. Pre-treatment of HCASMC with Cu(II)ATSM protected against the prooxidant 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 silencing. 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

UR - https://www.scopus.com/pages/publications/85016137144

U2 - 10.1038/s41598-016-0012-5

DO - 10.1038/s41598-016-0012-5

M3 - Article

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 7

ER -