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

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.

Are Astrocytes the Predominant Cell Type for Activation of Nrf2 in Aging and Neurodegeneration?

“…Many other Nrf2-inducing drugs are protective in animal models of Parkinson’s disease including triterpenoids (2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) derivatives) [ 69 , 70 ], curcumin [ 56 , 71 ], 3H-1,2-dithiole-3-thione [ 72 ], carnosic acid [ 73 ] and resveratrol [ 74 , 75 , 76 , 77 ] (see [ 2 ] for further compounds). Cu II (atsm) provides protection in multiple mouse models of Parkinson’s disease [ 78 ], and has recently be shown to activate Nrf2 in mice [ 79 ]. Cu II (atsm) is currently under investigation in a phase 1 clinical trial in Parkinson’s disease patients, including efficacy secondary outcome measures (NCT03204929; Table 2 ).…”

“…Cu II (atsm) improves motor function and extends survival in multiple mouse models of amyotrophic lateral sclerosis, including when administered post-symptom onset [ 180 , 181 , 182 , 183 , 184 , 185 ], and has recently been shown to activate Nrf2 in mice [ 79 ]. Cu II (atsm) is currently being investigated in a phase 1 clinical trial (NCT02870634), and a linked phase 1/2 extension trial (NCT03136809) in amyotrophic lateral sclerosis patients, both with efficacy secondary outcome measures ( Table 2 ).…”

Nexus between mitochondrial function, iron, copper and glutathione in Parkinson's disease

“…Cu II (atsm) has recently been shown to activate Nrf2 in heart (Srivastava et al, 2016), therefore Cu II (atsm) may be protective in PD models by activating Nrf2 in a copperdependent mechanism. These studies demonstrate that therapeutically increasing copper activates protective Nrf2 signalling.…”

Copper(ii) thiosemicarbazone complexes induce marked ROS accumulation and promote nrf2-mediated antioxidant response in highly resistant breast cancer cells

“…62,68 Diacetyl-bis(N4-methylthiosemicarbazonato)copper(II) [Cu II ATSM] was reported to induce expression of antioxidant enzymes through activation of nrf2 and its co-activator protein DJ-1 in response to oxidative stress both in vitro and in vivo. 69 Recently, Newton et al developed a copper(II)-TSC complex NSC689534 with ROSinducing and GSH-depleting properties which was subjected to microarray analysis. 62 It was demonstrated that NSC689534 activated several ROS-connected pathways, including a number of genes involved in nrf2-mediated oxidative stress.…”