Cadmium-induced endothelial dysfunction mediated by asymmetric dimethylarginine

Abstract

Cadmium (Cd) is a naturally occurring toxic heavy metal with no known essential biological functions. Exposure to Cd increases the risk of cardiovascular disease by disrupting vascular homeostasis at the endothelium. The aim of the study was to evaluate the effect of chronic low-dose Cd on vascular structure and function. Fifty adult male Sprague Dawley rats were grouped and assigned to one of two treatments for 14 weeks. The control group received normal water for 14 weeks while the Cd-treated group received 15 mg Cd/kg B.W. as CdCl₂ in water for 10 weeks. A subset of the Cd-treated group received 15 mg Cd/kg B.W. as CdCl₂ in water for 10 weeks followed by 4 weeks of normal water. Results show an overall decline in vascular function and structure. Withdrawal of Cd treatment showed a considerable restoration of vascular structure and vasorelaxation function. Additionally, asymmetric dimethylarginine (ADMA) bioavailability was found to be lowered over time. Interestingly, the expression of eNOS in the Cd-treated group was found to be significantly elevated during the exposure by more than 3-fold in comparison with that in the control group. This protein expression was similar to the control group after the withdrawal of Cd treatment. Taken together, the results suggest that ADMA, an eNOS inhibitor, may play a role in altering endothelial function in the presence of cadmium. In conclusion, the findings indicate that even at low doses, Cd leads to endothelial dysfunction mediated by ADMA.

Keywords: Asymmetric dimethylarginine (ADMA); Cadmium; Endothelial dysfunction; Endothelial nitric oxide synthase (eNOS).

Fig. 1

The effects of cadmium exposure on vasocontractility response of thoracic aorta of adult male SD rats to noradrenaline and acetylcholine. a Noradrenaline dose–response curve at week 10. b Acetylcholine dose–response curve at week 10. c Noradrenaline dose–response curve at week 14. d Acetylcholine dose–response curve at week 14. Data expressed as mean ± S.E.M. *P < 0.05, **P < 0.01

Fig. 2

The effects of chronic cadmium exposure on blood pressure in adult male SD rats. Changes in mean arterial pressure over 14 weeks. Data expressed as mean ± S.E.M.

Fig. 3

The effects of chronic cadmium exposure on bioavailability of ADMA in blood plasma of adult male SD rats. Data expressed as mean ± S.E.M. Columns sharing the same alphabet are statistically significant. a: P < 0.05, b: P < 0.05

Fig. 4

The effects of chronic cadmium exposure on aortic integrity of adult male SD rats. L indicates the luminal side showing aortic histological structure of the a control group with black arrows indicating a smooth, flat, and continuous endothelial layer of the TI and regular SMC arrangement in the TM; b Cd-treated group at week 10 with black arrow heads indicating denuded, discontinuous endothelium with irregular SMC in TM. Red arrow indicates formation of vacuoles, blue arrow indicates the hyperplasia of the SMC, and red arrow head indicates degeneration of the SMC; and c Cd-treated group at week 14 with black arrow indicating a continuous endothelial layer of the TI and regular organization of the SMC in the TM. (H & E, × 400)

Fig. 5

Effect of chronic cadmium exposure on eNOS expression. Fold change in eNOS expression in the aorta are represented above after correcting against α-actin. Data expressed as mean ± S.E.M, n = 4. *P < 0.05