Korean Circ J.  2013 Sep;43(9):581-591. 10.4070/kcj.2013.43.9.581.

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

Affiliations
  • 1Shawnee, KS, USA.
  • 2Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
  • 3Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. erickuo48@yahoo.com.tw

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.

Keyword

Kawasaki syndrome; Catecholamines; Mercury; Autoimmunity

MeSH Terms

Acrodynia
Arterial Pressure
Autoimmunity
Calcium
Calcium Signaling
Catechol O-Methyltransferase
Catecholamines
Child
Coronary Vessels
Diagnosis, Differential
Epinephrine
Heart Rate
Humans
Hydrazines
Hypertension
Inositol
Inositol 1,4,5-Trisphosphate
Inositol 1,4,5-Trisphosphate Receptors
Inositol Phosphates
Mucocutaneous Lymph Node Syndrome
Norepinephrine
Permeability
Phosphorylation
Polymorphism, Single Nucleotide
Powders
Relaxation
Risk Factors
S-Adenosylmethionine
Sarcolemma
Sarcoplasmic Reticulum
Tachycardia
Thimerosal
Thrombosis
Tooth
Tooth Eruption
Vaccines
Vasoconstrictor Agents
Vasodilation
Calcium
Catechol O-Methyltransferase
Catecholamines
Epinephrine
Hydrazines
Inositol
Inositol 1,4,5-Trisphosphate
Inositol 1,4,5-Trisphosphate Receptors
Inositol Phosphates
Norepinephrine
Powders
S-Adenosylmethionine
Thimerosal
Vaccines
Vasoconstrictor Agents

Figure

  • Fig. 1 An infant presenting with conjunctivitis and fissured lips, while the rash has spread over to the face-courtesy.

  • Fig. 2 Bilateral conjunctival injection without discharge-courtesy.

  • Fig. 3 The rash can spread around the body, and may also be intensified in the diaper region-courtesy.

  • Fig. 4 Erythematous extremities with extensive swelling-courtesy.

  • Fig. 5 Desquamation of the extremities typically occurs during the second or third week-courtesy.

  • Fig. 6 Reactivation of a previous vaccine site reaction during acute KS-courtesy. KS: Kawasaki syndrome.

  • Fig. 7 Swollen, erythematous palms with desquamation of a child with infantile acrodynia-courtesy of Dr. Weinstein.

  • Fig. 8 Swollen, erythematous soles of a child with infantile acrodynia-courtesy of Dr. Weinstein.


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