Cardiac chronotropic hypo-responsiveness and atrial fibrosis in rats chronically treated with lithium

The sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA) pump is responsible for regulating calcium (Ca 2+ ) within myocytes, with SERCA2a being the dominant isoform in cardiomyocytes.Its inhibitor, phospholamban (PLN), acts by decreasing the affinity of SERCA for Ca 2+ . Changes in the SERCA2a:PLN ratio can cause Ca 2+ dysregulation often seen in patients with dilated cardiomyopathy and heart failure. The enzyme glycogen synthase kinase-3 (GSK3) is known to downregulate SERCA function by decreasing the SERCA2a:PLN ratio. In this study, we sought to determine whether feeding mice low-dose lithium, a natural GSK3 inhibitor, would improve left ventricular SERCA function by altering the SERCA2a:PLN ratio. To this end, male wildtype C57BL/6J mice were fed low-dose lithium via drinking water (10 mg kg −1 day −1 LiCl for 6 weeks) and left ventricles were harvested. GSK3 activity was significantly reduced in LiClfed versus control-fed mice. The apparent affinity of SERCA for Ca 2+ was also increased (pCa 50 ; control, 6.09 ± 0.03 versus LiCl, 6.26 ± 0.04, P < 0.0001) along with a 2.0-fold increase in SERCA2a:PLN ratio in LiCl-fed versus control-fed mice. These findings suggest that low-dose lithium supplementation can improve SERCA function by increasing the SERCA2a:PLN ratio.Future studies in murine preclinical models will determine whether GSK3 inhibition via low-dose lithium could be a potential therapeutic strategy for dilated cardiomyopathy and heart failure. K E Y W O R D Scalcium, cardiac muscle, GSK3, lithium supplementation, phospholamban, SERCA 1 wileyonlinelibrary.com/journal/eph Experimental Physiology. 2020;105:666-675.

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“…This was not surprising because we used a dose of lithium well below that previously used by Moradi et al. (2019) (2.5 g kg −1 ).…”

Section: Discussionmentioning

confidence: 81%

“…A recent study performed by Moradi et al. (2019), looking at the cardiac chronotropic effects of chronic lithium treatment in Wistar rats, showed an increase in atrial fibrosis. Thus, we performed trichrome staining of our mouse hearts and saw no differences in fibrosis in the lithium‐fed group compared with the control‐fed group.…”

Section: Discussionmentioning

confidence: 96%

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Hamstra

Kurgan

Baranowski

et al. 2020

Experimental Physiology

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“…The fibrosis in cardiac tissues of rats after chronic lithium therapy was also reported by Moradi et al who referred this atrial fibrosis to the increase in the expression of collagen I, alpha 1 gene. 49 Moreover, Nikolić-Kokić et al 50 reported similar morphological and antioxidant enzymes function changes in rat heart treated with other atypical antipsychotics including clozapine, ziprasidone, and sertindole.…”

Section: Discussionmentioning

confidence: 92%

The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine

2020

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Lithium is one of the most powerful and commonly used medications for the treatment of various psychiatric diseases, especially bipolar disorder. However, it has a narrow therapeutic index with toxic effects on various organs. There are several case reports of lithium-induced arrhythmia and ischemia. The current work aimed to study the toxic effects of lithium on the heart of adult albino rats and its molecular mechanisms and the ameliorating effect of N-acetyl cysteine (NAC). Sixty adult male Wistar albino rats were classified into four groups; control, NAC-treated received NAC 500 mg/kg/week dissolved in 1 ml 0.9% sodium chloride intraperitoneal, lithium-treated received 52.5 mg/kg/day of lithium carbonate dissolved in 1 ml 0.9% sodium chloride orally by gavage, and lithium-and-NAC-treated (group IV) received lithium and NAC in the previous doses. After 12 weeks, the rats of group III showed a significant accumulation of ascites and a decrease in the mean arterial blood pressure and electrocardiographic (ECG) findings of ischemia and arrhythmia. In addition, there was an elevation in cardiac biomarkers creatine kinase MB (CK-MB), cardiac troponin I (cTnI), and several histological lesions with a significant increase in the area % of Van Gieson, endothelial nitric oxide synthase (eNOS), and 8-hydroxy-2′-deoxyguanosine (8-OHdG) immunoreaction. There was significant upregulation of microRNA-1, microRNA-21 (miRNA-21), and microRNA-29 (miRNA-29). MiRNA-21 was strongly positively correlated to the area % of 8-OHdG, while miRNA-29 was strongly positively correlated to the area % of Van Gieson staining. NAC significantly improved the cardiotoxic effects of lithium. Being a nontoxic and safe antioxidant, NAC can be used to ameliorate lithium-induced cardiac injury.

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“…It can inhibit GSK‐3 β and induce the nuclear translocation of β‐catenin, thus activating the pathway 21 . In Male Wistar albino rats model, after given lithium chloride orally for 2 or 3 months, the expression of atrial Col1a1 mRNA was significantly increased 7 . To further verify our results, we used different concentrations of LiCl to stimulate HVFs in POP group, and found that with the increase of LiCl concentration, the nuclear transfer of β‐catenin increased, and cell proliferation and collagen I expression increased.…”

Section: Discussionmentioning

confidence: 99%

“…Lithium chloride, an agonist for β-catenin by inhibiting GSK-3β activity, has been reported to increase the expression of collagen I in animal and cell experiments. [6][7][8] To further understanding the role of β-catenin in the development of POP, we used primary-cultured HVFs of POP women and non-POP women to assess the effect of β-catenin on proliferation and function of HVFs. We hypothesized that β-catenin is involved in the pathophysiology of POP via the inhibition of vaginal fibroblast proliferation and collagen synthesis, a condition that can be reversed by the administration of lithium chloride.…”

Section: Introductionmentioning

confidence: 99%

Effects of the decrease of β‐catenin expression on human vaginal fibroblasts of women with pelvic organ prolapse

Gong

Yang

Jin

et al. 2021

J of Obstet and Gynaecol

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Background Pelvic organ prolapse (POP) lowers the quality of life in elderly women, and there have been no studies on its role in the pathogenesis of POP. The purpose of this study is to investigate the effect of β‐catenin on proliferation and collagen anabolism in human vaginal fibroblasts (HVFs). Materials and Methods The adherence and differential adherence methods were used to culture and purify HVFs. RNA interference was applied to knockdown β‐catenin and lithium chloride was used to activate Wnt/β‐catenin signaling pathway. β‐catenin nuclear translocation was tested by immunofluorescence, and HVF proliferation was detected by performing MTT assays. Results The expression of β‐catenin, phosphorylated‐β‐catenin, phosphorylated‐glycogen synthase kinase 3β (p‐GSK3β), collagen I, matrix metalloproteinase 2 (MMP2), and tissue‐derived inhibitors of metalloproteinases 2 (TIMP2) was assessed by western blot analysis. The expression of β‐catenin and collagen I was lower in HVFs of POP group than that of control group. The proliferation rate of HVFs in POP group was lower than that in control group. Knockdown of β‐catenin decreased the cell proliferation rate and the expression of collagen I. Lithium chloride can activate the Wnt/β‐catenin signaling pathway. Conclusion β‐catenin participates in the proliferation and collagen I synthesis of HVFs. The decrease of β‐catenin expression may be closely related to the occurrence, and development of POP. LiCl can activate the Wnt/β‐catenin signaling pathway in HVFs and thus increase HVFs proliferation and collagen synthesis.

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Cardiac chronotropic hypo-responsiveness and atrial fibrosis in rats chronically treated with lithium

Cited by 5 publications

References 16 publications

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

Low‐dose lithium feeding increases the SERCA2a‐to‐phospholamban ratio, improving SERCA function in murine left ventricles

The molecular mechanisms of lithium-induced cardiotoxicity in male rats and its amelioration by N-acetyl cysteine

Effects of the decrease of β‐catenin expression on human vaginal fibroblasts of women with pelvic organ prolapse

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