Trivalent methylated metabolites of
arsenic,
monomethylarsonous acid (
MMA(III)) and
dimethylarsinous acid (DMA(III)), have been found highly reactive and toxic in various cells and in vivo animal models, suggesting their roles in the
arsenic-associated toxicity. However, their effects on cardiovascular system including blood cells, one of the most important targets for
arsenic toxicity, remain poorly understood. Here we found that
MMA(III) and DMA(III) could induce procoagulant activity and apoptosis in platelets, which play key roles in the development of various
cardiovascular diseases (CVDs) through excessive
thrombus formation. In freshly isolated human platelets, treatment of
MMA(III) resulted in
phosphatidylserine (PS) exposure, a hallmark of procoagulant activation, accompanied by distinctive apoptotic features including mitochondrial membrane potential disruption,
cytochrome c release, and
caspase-3 activation. These procoagulant activation and apoptotic features were found to be mediated by the depletion of
protein thiol and intracellular
ATP, and flippase inhibition by
MMA(III), while the intracellular
calcium increase or
reactive oxygen species generation was not involved. Importantly, increased platelet procoagulant activity by
MMA(III) resulted in enhanced blood coagulation and excessive
thrombus formation in a rat in vivo
venous thrombosis model. DMA(III) also induced PS-exposure with apoptotic features mediated by
protein thiol depletion, which resulted in enhanced
thrombin generation. In summary, we believe that this study provides an important evidence for the role of trivalent methylated
arsenic metabolites in
arsenic-associated CVDs, giving a novel insight into the role of platelet apoptosis in toxicant-induced cardiovascular toxicity.