Zinc Homeostasis in Platelet-Related Diseases.

Elmina Mammadova-Bach,Attila Braun

doi:10.3390/ijms20215258

Abstract

Zn2+ deficiency in the human population is frequent in underdeveloped countries. Worldwide, approximatively 2 billion people consume Zn2+-deficient diets, accounting for 1–4% of deaths each year, mainly in infants with a compromised immune system. Depending on the severity of Zn2+ deficiency, clinical symptoms are associated with impaired wound healing, alopecia, diarrhea, poor growth, dysfunction of the immune and nervous system with congenital abnormalities and bleeding disorders. Poor nutritional Zn2+ status in patients with metastatic squamous cell carcinoma or with advanced non-Hodgkin lymphoma, was accompanied by cutaneous bleeding and platelet dysfunction. Forcing Zn2+ uptake in the gut using different nutritional supplementation of Zn2+ could ameliorate many of these pathological symptoms in humans. Feeding adult rodents with a low Zn2+ diet caused poor platelet aggregation and increased bleeding tendency, thereby attracting great scientific interest in investigating the role of Zn2+ in hemostasis. Storage protein metallothionein maintains or releases Zn2+ in the cytoplasm, and the dynamic change of this cytoplasmic Zn2+ pool is regulated by the redox status of the cell. An increase of labile Zn2+ pool can be toxic for the cells, and therefore cytoplasmic Zn2+ levels are tightly regulated by several Zn2+ transporters located on the cell surface and also on the intracellular membrane of Zn2+ storage organelles, such as secretory vesicles, endoplasmic reticulum or Golgi apparatus. Although Zn2+ is a critical cofactor for more than 2000 transcription factors and 300 enzymes, regulating cell differentiation, proliferation, and basic metabolic functions of the cells, the molecular mechanisms of Zn2+ transport and the physiological role of Zn2+ store in megakaryocyte and platelet function remain elusive. In this review, we summarize the contribution of extracellular or intracellular Zn2+ to megakaryocyte and platelet function and discuss the consequences of dysregulated Zn2+ homeostasis in platelet-related diseases by focusing on thrombosis, ischemic stroke and storage pool diseases.

Highlights

Zinc (Zn2+) is the second most important trace metal in the body
We propose that platelets from gray platelet syndrome (GPS) mouse model and human patients have a strongly reduced Zn2+ store, which influences platelet Zn2+ homeostasis and fibrin clot formation
Taking into account these findings from the limited number of patients and mouse models with granule storage deficiency or granule release defects, it worth postulating that Zn2+ homeostasis could be strongly impaired in patients with platelet granular abnormalities

Summary

Introduction

Zinc (Zn2+) is the second most important trace metal in the body. Zn2+ enters into the organism through dietary consummation and plays a critical role in many biological processes including development, proliferation, differentiation, cell metabolism, insulin synthesis and secretion, immune function, regulation of DNA synthesis and genomic stability [1,2]. Resting platelets can uptake Zn2+ from the blood plasma and store it, indicating the existence of active Zn2+ transport and storage mechanisms [15,25,26]. Deletion of TRPM7 kinase activity in mice significantly reduces SOCE in platelets, and protected mice from ischemic brain insults, indicating that the increased kinase function, rather than its channel function of TRPM7, plays an important role in ischemic stroke [120].

Results

Conclusion