Sex-dependent effects of acute cobalt treatment in Langendorff perfused adult rat hearts and human adult cardiac fibroblasts

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Cameron Ruiz, Miren and Roberts, Charlotte and Cunningham, Eve and Pickard, Benjamin and MacQuaide, Niall and Currie, Susan (2026) Sex-dependent effects of acute cobalt treatment in Langendorff perfused adult rat hearts and human adult cardiac fibroblasts. In: Scottish Cardiovascular Forum 2026, 2026-03-21 - 2026-03-21, University of Glasgow.

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Abstract

Cobalt exposure from metal-on-metal hip arthroplasties has been associated with cardiomyopathy and interstitial fibrosis, but underlying mechanisms and potential sexdependent differences remain unclear. This study investigated effects of cobalt chloride (CoCl₂) on male and female working rat hearts and human cardiac fibroblasts (HCFs). Adult rat hearts were Langendorff-perfused with oxygenated Tyrode’s solution in the absence or presence of CoCl₂ (100 μM) for 1h. Following perfusion, hearts were sectioned for immunofluorescence and immunoblot analysis of Hypoxia-inducible factor 1α (HIF-1α) and αsmooth muscle actin (α-SMA). Primary male and female HCFs were treated with CoCl₂ (1–300 μM) for 48–72h, TGFβ (pro-fibrotic stimulus), or lep untreated. Viability was assessed using MTT assays, migration by scratch assay, and HIF-1α and α-SMA expression by western blot following 72h treatments to evaluate phenotype and fibrosis. Cobalt treatment induced earlier cessation of beating in male (within 15-20 minutes) compared to female (20-40 minutes) Langendorff-perfused hearts, whereas controls remained beating throughout. In cobalt-treated male lep ventricular tissue HIF-1α expression increased while α-SMA expression was unchanged, consistent with immunofluorescence analysis. Aper 72 hours, female HCF viability was significantly reduced at all CoCl2 concentrations, whereas male viability decreased only at 100μM (p<0.005) and 300μM (p<0.005). In migration assays, male HCF wound closure was impaired at 100 μM (p<0.05 at 8 h) and 300μM (p<0.05 at 3 h; p<0.005 at 8 h; p<0.001 at 24 h), while females were affected only at 300μM (p<0.001 at 8 h). HIF-1α expression increased while α-SMA decreased in male HCFs at all concentrations (p<0.001), but α-SMA remained unaffected in females. These findings demonstrate sex-dependent differences in the effects of cobalt on HCFs and isolated working rat hearts, with potential implications for our future understanding of cobaltinduced cardiac dysfunction in patients. Further research is necessary to fully elucidate the underlying cellular mechanisms responsible.

ORCID iDs

Cameron Ruiz, Miren, Roberts, Charlotte, Cunningham, Eve, Pickard, Benjamin ORCID logoORCID: https://orcid.org/0000-0002-2374-6329, MacQuaide, Niall and Currie, Susan ORCID logoORCID: https://orcid.org/0000-0002-4237-4428;
CORE (COnnecting REpositories)