Cobalt Administration Causes Reduced Contractility with Parallel Increases in TRPC6 and TRPM7 Transporter Protein Expression in Adult Rat Hearts

Sarunya Laovitthayanggoon,Margaret Macdonald,Claire Mccluskey,Catherine J Henderson,Rothwelle J Tate,M Helen Grant,Susan Currie

doi:10.1007/s12012-018-9498-3

Sarunya Laovitthayanggoon, Margaret Macdonald + Show 5 more

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https://doi.org/10.1007/s12012-018-9498-3

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Journal: Cardiovascular toxicology	Publication Date: Dec 6, 2018
Citations: 7	License type: open-access

Affiliation: University of Strathclyde

Abstract

Exposure to circulating cobalt (Co2+) in patients with metal-on-metal orthopaedic hip implants has been linked to cardiotoxicity but the underlying mechanism(s) remain undefined. The aim of the current study was to examine the effects of Co2+ on the heart in vivo and specifically on cardiac fibroblasts in vitro. Adult male rats were treated with CoCl2 (1 mg/kg) for either 7 days or 28 days. Inductively coupled plasma mass spectrometry (ICP-MS) was used to measure Co2+ uptake into various organs of the body. Co2+ accumulated in the heart over time with significant levels evident after only 7 days of treatment. There was no evidence of cardiac remodelling following Co2+ treatment as assessed by heart weight:body weight and left ventricular weight:body weight. However, a decrease in fractional shortening, as measured using echocardiography, was observed after 28 days of Co2+ treatment. This was accompanied by increased protein expression of the ion transient receptor potential (TRP) channels TRPC6 and TRPM7 as assessed by quantitative immunoblotting of whole cardiac homogenates. Uptake of Co2+ specifically into rat cardiac fibroblasts was measured over 72 h and was shown to dramatically increase with increasing concentrations of applied CoCl2. Expression levels of TRPC6 and TRPM7 proteins were both significantly elevated in these cells following Co2+ treatment. In conclusion, Co2+ rapidly accumulates to significant levels in the heart causing compromised contractility in the absence of any overt cardiac remodelling. TRPC6 and TRPM7 expression levels are significantly altered in the heart following Co2+ treatment and this may contribute to the Co2+-induced cardiotoxicity observed over time.

Highlights

Cardiotoxicity is the most frequently encountered adverse effect contributing to attrition of new candidate pharmaceuticals, but it has not often been associated with use of medical devices
At 72 h, there was no obvious effect of C o2+ on Divalent metal transporter channel 1 (DMT1) expression; both TRPC6 and TRPM7 proteins were again significantly increased in the presence of CoCl2 (Fig. 6a, b). This is the first time that Co2+-induced events in the whole heart have been linked with effects that are induced in the non-contractile cells of the heart. Co2+ is rapidly taken up and distributed throughout all the main organs of the body with significant levels found in the heart after just 7 days of treatment (Fig. 2)
Cardiac function is altered after 28 days of treatment with C oCl2 (1 mg/kg) whereby % fractional shortening is significantly reduced (Fig. 3a)

Summary

Introduction

Cardiotoxicity is the most frequently encountered adverse effect contributing to attrition of new candidate pharmaceuticals, but it has not often been associated with use of medical devices. The most notorious of these limitations in recent years are the adverse effects associated with metal-on-metal (MoM) hip articulations, made of CoCr alloy, which have led to several implants being removed from use following release of warning alerts by the medicines and healthcare products regulatory agency (MHRA) [1]. Wear of these medical devices causes formation and release of nanoparticulate debris of CoCr, and metal ions in patients. Most of the defective MoM designs have been removed from the

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