Increased protein phosphatase 5 expression in inflammation-induced left ventricular dysfunction in rats

BMC Cardiovascular Disorders

Research

Regina Le Roux¹  Colleen A. Flanagan¹  Serena Fourie¹  Aletta M. E. Millen¹  Sulè Gunter¹  Lebogang Mokotedi¹  Ashmeetha Manilall¹ 

[1] Integrated Molecular Physiology Research Initiative, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193, Johannesburg, South Africa;

关键词: Left ventricular diastolic dysfunction;    Microvascular inflammation;    Titin phosphorylation;    Tumor necrosis factor-alpha inhibitor;    Protein phosphatase 5;   

DOI  :  10.1186/s12872-022-02977-z

 received in 2022-04-28, accepted in 2022-11-25,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundTitin phosphorylation contributes to left ventricular (LV) diastolic dysfunction. The independent effects of inflammation on the molecular pathways that regulate titin phosphorylation are unclear.MethodsWe investigated the effects of collagen-induced inflammation and subsequent tumor necrosis factor-α (TNF-α) inhibition on mRNA expression of genes involved in regulating titin phosphorylation in 70 Sprague-Dawley rats. LV diastolic function was assessed with echocardiography. Circulating inflammatory markers were quantified by enzyme-linked immunosorbent assay and relative LV gene expression was assessed by Taqman® polymerase chain reaction. Differences in normally distributed variables between the groups were determined by two-way analysis of variance (ANOVA), followed by Tukey post-hoc tests. For non-normally distributed variables, group differences were determined by Kruskal–Wallis tests.ResultsCollagen inoculation increased LV relative mRNA expression of vascular cell adhesion molecule 1 (VCAM1), pentraxin 3 (PTX3), and inducible nitric oxide synthase (iNOS) compared to controls, indicating local microvascular inflammation. Collagen inoculation decreased soluble guanylate cyclase alpha-2 (sGCα2) and soluble guanylate cyclase beta-2 (sGCβ2) expression, suggesting downregulation of nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling. Inhibiting TNF-α prevented collagen-induced changes in VCAM1, iNOS, sGCα2 and sGCβ2 expression. Collagen inoculation increased protein phosphatase 5 (PP5) expression. Like LV diastolic dysfunction, increased PP5 expression was not prevented by TNF-α inhibition.ConclusionInflammation-induced LV diastolic dysfunction may be mediated by a TNF-α-independent increase in PP5 expression and dephosphorylation of the N2-Bus stretch element of titin, rather than by TNF-α-induced downregulation of NO-sGC-cGMP pathway-dependent titin phosphorylation. The steady rise in number of patients with inflammation-induced diastolic dysfunction, coupled with low success rates of current therapies warrants a better understanding of the systemic signals and molecular pathways responsible for decreased titin phosphorylation in development of LV diastolic dysfunction. The therapeutic potential of inhibiting PP5 upregulation in LV diastolic dysfunction requires investigation.

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

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