Abstract Cadmium (Cd) is a non-essential heavy metal with high toxicity potential. Humans are exposed to Cd present in diet, polluted air, and cigarette smoke. Cd exposure has been associated with increased risk of chronic diseases, including hypertension, atherosclerosis, diabetes, and nephropathy, all of which could be attributable to dysfunctional endothelial and smooth muscle cells. Cd toxicity is correlated with increased reactive oxygen formation and depletion of antioxidants, resulting in an oxidative stress. Chelation of Cd has proved useful in the removal of the Cd burden. However, several chelating agents cause side effects in clinical usage. Recent studies have shown that the antioxidant compounds curcumin and tetrahydrocurcumin can alleviate vascular dysfunction and high blood pressure caused by Cd toxicity. In chronic Cd exposure, these antioxidants protect vascular endothelium by increasing nitric oxide (NO•) bioavailability and improving vascular function. Antioxidant activity against Cd intoxication results directly and/or indirectly through free radical scavenging, metal chelation, enhanced expression of the antioxidant defense system, regulation of inflammatory enzymes, increase in NO• bioavailability, and reduction of gastrointestinal absorption and tissue Cd accumulation. This review summarizes current knowledge of Cd-induced oxidative stress and cardiovascular dysfunction and a possible protective effect conferred by the antioxidants curcumin and tetrahydrocurcumin.

Conclusion Because Cd is not degraded in the environment and enters the food chain, the risk of human exposure to Cd and toxicity is constantly rising. Cd is a persistent and widespread pollutant that affects the structure and function of several organs by generating oxidative stress. This review provides an insight into the role of reactive species in Cd-induced toxicity. Metal-induced oxidative damage is driven by the formation of ROS/RNS, including O 2 ●−, OH•, NO• and ONOO−. The sources of free radicals within vascular cells are NADPH oxidases, xanthine oxidase, mitochondrial electron leakage, and uncoupled eNOS. Cd exposure increases risk of cardiovascular diseases including hypertension, atherosclerosis, nephropathy, and diabetes. Cd affects the cardiovascular system by altering cardiovascular structure and function. Endothelial and vascular smooth muscle cells are the major targets of Cd toxicity. Cd chelation has been suggested to be of use in the treatment of Cd toxicity. However, most chelators have severe adverse effects and inconvenient modes of administration. Combined therapy with more than one chelator and/or with antioxidants may be more effective in reducing Cd toxicity. Recent studies provide evidence that curcumin and tetrahydrocurcumin, polyphenol compounds with strong antioxidant activities, can protect against hypertension, vascular dysfunction, arterial stiffness, and vascular remodeling during Cd intoxication in mice. The mechanisms contributing to their effectiveness are their free radical scavenging effect, alleviation of oxidative stress, restoration of the antioxidant GSH, and probable chelation effect resulting in reduction of Cd load in tissues. All of these effects lead to a reduction of high blood pressure and improvement of vascular function in our study. Although curcumin and tetrahydrocurcumin protect against Cd toxicity, the therapeutic effect of these two compounds after Cd exposure is another important aspect and merits further detailed investigation. In conclusion, the results from previous studies, together with the findings presented here, suggest a beneficial effect of curcumin and tetrahydrocurcumin. These two antioxidants may be used as a dietary supplement following heavy metal exposure, or as a complimentary chelating agent to increase the efficacy of chelators in order to minimize metal toxicity. However, evidence to support the use of natural antioxidants in clinical treatment is still lacking. Therefore, further studies are needed to explore the exact mechanisms underlying the vascular protective effects of these antioxidants, and also to define the proper dosage and duration of treatment in humans.

Acknowledgments The project was supported by grants from the National Research Council of Thailand, the Khon Kaen University Research Fund, the Invitation Research Fund, Faculty of Medicine, Khon Kaen University and the Thailand Research Fund. The authors thank Dr. Justin T. Reese for suggestions and language editing of the manuscript.

Conflict of Interest The authors declare no conflict of interest.

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