Mercury Promotes Catecholamines Which Potentiate Mercurial Autoimmunity and Vasodilation: Implications for Inositol 1,4,5-Triphosphate 3-Kinase C Susceptibility in Kawasaki Syndrome

Abstract

Previously, we reviewed biological evidence that mercury could induce autoimmunity and coronary arterial wall relaxation as observed in Kawasaki syndrome (KS) through its effects on calcium signaling, and that inositol 1,4,5-triphosphate 3-kinase C (ITPKC) susceptibility in KS would predispose patients to mercury by increasing Ca2+ release. Hg2+ sensitizes inositol 1,4,5-triphosphate (IP3) receptors at low doses, which release Ca2+ from intracellular stores in the sarcoplasmic reticulum, resulting in delayed, repetitive calcium influx. ITPKC prevents IP3 from triggering IP3 receptors to release calcium by converting IP3 to inositol 1,3,4,5-tetrakisphosphate. Defective IP3 phosphorylation resulting from reduced genetic expressions of ITPKC in KS would promote IP3, which increases Ca2+ release. Hg2+ increases catecholamine levels through the inhibition of S-adenosylmethionine and subsequently catechol-O-methyltransferase (COMT), while a single nucleotide polymorphism of the COMT gene (rs769224) was recently found to be significantly associated with the development of coronary artery lesions in KS. Accumulation of norepinephrine or epinephrine would potentiate Hg2+-induced calcium influx by increasing IP3 production and increasing the permeability of cardiac sarcolemma to Ca2+. Norepinephrine and epinephrine also promote the secretion of atrial natriuretic peptide, a potent vasodilator that suppresses the release of vasoconstrictors. Elevated catecholamine levels can induce hypertension and tachycardia, while increased arterial pressure and a rapid heart rate would promote arterial vasodilation and subsequent fatal thromboses, particularly in tandem. Genetic risk factors may explain why only a susceptible subset of children develops KS although mercury exposure from methylmercury in fish or thimerosal in pediatric vaccines is nearly ubiquitous. During the infantile acrodynia epidemic, only 1 in 500 children developed acrodynia whereas mercury exposure was very common due to the use of teething powders. This hypothesis mirrors the leading theory for KS in which a widespread infection only induces KS in susceptible children. Acrodynia can mimic the clinical picture of KS, leading to its inclusion in the differential diagnosis for KS. Catecholamine levels are often elevated in acrodynia and may also play a role in KS. We conclude that KS may be the acute febrile form of acrodynia.

Glyphosate Use Predicts ADHD Hospital Discharges in the Healthcare Cost and Utilization Project Net (HCUPnet): A Two-Way Fixed-Effects Analysis

“…It should also be mentioned that heavy metal exposures may exacerbate parasympathetic dominant states [ 107 , 108 ]; interestingly, it may be the case that levels of these heavy metals may be elevated in ASD subjects out of a consequence of this heightened parasympathetic state induced in utero. In other words, the ASD phenotype, through reduced baseline sympathetic activation, may be better able to tolerate higher endogenous levels of such toxins [ 109 ], whereas sympathetic activation in non-ASD subjects may aggravate the toxicity of heavy metal exposures [ 110 , 111 ]. The current N 2 O hypothesis therefore supports the notion of autonomic dysregulation in ASD and suggests that the origin of such dysregulation may occur during gestation, although more comprehensive intergenerational research is needed.…”

Pediatric Mercury Intoxication Mimicking Pheochromocytoma

“…Hg binding to co-enzyme S-adenosyl methionine results in inactivation of catechol-O-methyltransferase required for degradation of catecholamines ( 7 ). This leads to increased levels of catecholamine and catecholamine metabolites, which clinically mimics pheochromocytoma.…”

A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease

“…The many genes involved in KD [42] probably interact with one another to increase the risk for the disease and for its complications [4]. Patients with the combined rs28493229 polymorphism in the ITPKC gene encoding IP 3 3-kinase C and the rs113420705 polymorphism in the CASP3 gene encoding caspase-3 had a higher risk of resistance to intravenous immunoglobulins, while a polymorphism in only one of the two genes was not associated with the response to the treatment [20,21,58,60,70].…”

“…The prevalence of KD in children younger than 5 years is the highest in Japan, followed by Korea and Taiwan. The incidence in Japan is 265/ 100,000 [3] and more than 1 in every 100 Japanese children will develop KD [4]. The incidence is 10-20 times higher than in Western countries.…”

“…KD then develops into a localized inflammation focused primarily at the coronary arteries, resulting in coronary artery dilatation, aneurysms, fistulas and stenosis, which in turn can lead to sudden death [5,7,8]. KD has replaced acute rheumatic fever as the leading cause of acquired pediatric heart disease in developed countries [4,9].…”