Cardiovascular Effects of Environmental Metal Antimony: Redox Dyshomeostasis as the Key Pathogenic Driver

Abstract

Significance: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals, and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed. Recent Advances: Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized. Critical Issues: Several epidemiological studies have revealed the significant deleterious effects of antimony on the cardiovascular system in the absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis. Future Directions: More direct evidence from preclinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs. Antioxid. Redox Signal. 38, 803-823.

Keywords: antimony toxicity; cardiovascular diseases; metal cardiotoxicity; redox imbalance.

FIG. 1.

Outline of the key information of this review. Sb exits naturally, but is not an essential metal for human, however, it can be used for military and medical stuffs and in daily-used plastic materials, and it contaminates the environments, including air, soil, plants, and food. Therefore, human is exposed occupationally, medically, and environmentally. The harmful effect of Sb includes CV impact (up, right box) and other non-CV effects (bottom box). CV, cardiovascular; Sb, antimony.

FIG. 2.

Short summary of Sb-induced cardiotoxicities. In three boxes, the key cardiotoxicity induced by Sb were summarized as EKG and echo measurements as well as cardiac arrest and mortality rate due to cardiac failure, based on publications (Badr et al, ; Daadaa et al, ; Frustaci et al, ; Gupta, ; Pandey et al, ; Ribeiro et al, ; Rijal et al, ; Schnorr et al, ; Shiue, ; Shrivastava et al, ; Thakur et al, 1998). Echo, echocardiographic; EKG, electrocardiogram.

FIG. 3.

Comparisons of blood Sb levels after single or multiple treatments among species. (A) Mimic eliminating pattern of plasma Sb levels in patients at before and 1, 2, 4, and 6 h after a single intramuscular infiltration of MA to determine the peak and decrease to 6 h with an estimation of the half-life of Sb as ½ h. This mimic time-course curves were roughly made based on the publication (de Aguiar et al, 2018). (B) Total Sb levels in the whole blood of a male patient with CL during and after administration of MA daily at 5 mg/kg body weight for 60 days, which was mimicked based on the publication (Miekeley et al, 2002) to compare with other panels in this figure. (C) The mimic time-course curve of the Sb concentrations in the blood of Schistosoma mansoni-infected mice at different times (0.5 h to 15 days) after a single i.p. injection of 5 mg/kg body weight Sb(III) drug, based on the publication (Molokhia and Smith, 1969). The highest concentration of Sb was at 8 h and quickly decreased to very low beyond 4 days and almost zero at day 16. (D) The mimic time-course of the whole blood Sb levels in male rats after a single i.v. injection of MA (75 mg/kg body weight), showing a sharp fall at (t_1/2 = 0.6 h), until 24 h, based on the publication (Coelho et al, 2014). (E) A mimic time-course curve of blood Sb concentrations from 6 male rats treated with MA (300 mg/kg body weight, subcutaneous) during 21 consecutive days (gray box) and an additional 21 days after the last dose (light blue box), based on the publication (Coelho et al, 2014). (F) Concentrations of antimony (μg/g) in rat tissues 24 h and 21 days after a 21-day treatment with MA at the same dose as panel (E) (Coelho et al, 2014). Accumulation of Sb in the heart belongs to the low group of Sb accumulating tissues, indicated by the blue arrow. CL, cutaneous leishmaniasis; i.p., intraperitoneal; i.v., intravenous; MA, meglumine antimoniate.

FIG. 4.

Conceptual summary of a few models for abiotic and biotic oxidation of Sb(III) and reduction of Sb(V). , sunlight; , UV or ionizing radiation.

FIG. 5.

Sb-induced adaptive or hormetic response or harmful effects. The amounts of Sb-induced ROS and RNS determine the cell sensitivity to the subsequent stress-induced toxicity. When cells are exposed to a small dose of Sb, which induces a small amount of ROS and/or RNS that are not to kill the cell but stimulate the production of cellular response proteins and enzymes, and consequently, the cells become resistant to a subsequent dose of Sb or other stress, as illustrated in the left panel. In contrast, when cells are exposed to a high dose of Sb, which induces a large amount of ROS and/or RNS beyond the capacity of the cellular endogenous defense system, and even exhausted the endogenous defense enzymes and proteins similar to that illustrated in the right panel, these cells will be lethal or become more sensitive to subsequent stress even though these cells still survive. This hypothetic summary was based on publications (Gu et al, ; Losler et al, ; Snawder et al, ; Su et al, 2022). RNS, reactive nitrogen species; ROS, reactive oxygen species.

FIG. 6.

A cartoon representative of the proposed interaction between LdG6PDH and LdTryR, and how its interaction status leads to the redox balance and dyshomeostasis, in Leishmania donovani. This was adopted from the publication (Ghosh et al, 2017). MMR, metalloid-mediated ROS; TMC, thiol metalloid complex.