Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment

Abstract

The use of Doxorubicin (DOXO), a potent antineoplastic agent, is limited by the development of cardiotoxicity. DOXO-induced cardiotoxicity is multifactorial, although alterations in calcium homeostasis, seem to be involved. Since even the Connexin43 (Cx43) plays a pivotal role in these two phenomena, in this study we have analyzed the effects of DOXO on Cx43 expression and localization. Damage caused by anthracyclines on cardiomyocytes is immediate after each injection, in the present study we used a short-term model of DOXO-induced cardiomyopathy. C57BL/6j female mice were randomly divided in groups and injected with DOXO (2 or 10 mg/kg i.p.) for 1–3 or 7 days once every other day. Cardiac function was assessed by Echocardiography. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII) and phospholamban (PLB) expression were assessed by Western blot analysis, intracellular [Ca2+] were detected spectrofluorometrically by means of Fura-2 pentakis (acetoxymethyl) ester (FURA-2AM), and Cx43 and pCx43 expression and localization was analyzed by Western blot and confirmed by immunofluorescence analysis. DOXO induces impairment in Ca2+ homeostasis, already evident after a single administration, and affects Cx43 expression and localization. Our data suggest that DOXO-induced alterations in Ca2+ homeostasis causes in the cells the induction of compensatory mechanisms until a certain threshold, above which cardiac injury is triggered.

Benzo[a]pyrene‐decreased gap junctional intercellular communication via calcium/calmodulin signaling increases apoptosis in TM4 cells

“…Lurtz and Louis reported that the gap junction‐mediated cell‐to‐cell transfer of dye between lens epithelial cells or Cx43‐transfected HeLa Cells was inhibited by Ca 2+ /CaM (Lurtz & Louis, , ). Moreover, the rapid onset of GJIC inhibition (within seconds) suggested that this inhibition was mediated by the direct interaction of CaM with one or more of the lens connexins, rather than by the action of a CaM‐dependent protein kinase (Lurtz & Louis, , ; Pecoraro et al, ). According to our results and those of previous studies, we hypothesize that CaM is involved in the decrease of GJIC induced by BaP via directly interacting with Cx43, rather than by altering the expression of Cx43 protein.…”

“…Cx43 phosphorylation is mechanistically linked to gap junctional communication, and phosphorylation of Cx43 at different sites controls gap junction assembly, gap junction size and gap junction turnover (Zou et al, ). In addition, intracellular Ca 2+ homeostasis is important in the maintenance of normal cellular functions in response to extracellular stimuli, and is also a regulatory mechanism of GJIC (Pecoraro et al, ; Zhou et al, ). However, whether BaP can induce changes in GJIC level in Sertoli cells through the two mechanisms described above remains unclear.…”

Early Electrocardiographic Indices for Predicting Chronic Doxorubicin-Induced Cardiotoxicity: Retrospective Case Series Study

“…Several studies reported on the widening of the QRS complex following DOX exposure, which suggested intraventricular conduction defects due to myocardial ultrastructural changes, such as intercalated disc separation, myo brillar derangement, vacuolization, and interstitial edema [11,17]. Furthermore, Pecoraro et al demonstrated that DOX treatment resulted in markedly reduced expression and function of connexin-43, which potentially leads to slower conduction velocity and loss of rapid electrical synchronization throughout the myocardium [18]. However, there are inconsistent ndings in the literature.…”

Impact of corvitin and alpha-ketoglutarate on heart morphology, expression and activity of matrix metalloproteinases 2/9 in the heart of rats with doxorubicin-induced cardiomyopathy

“…Despite the enormous amount of research in this area, the exact molecular mechanisms underlying the toxic effects of doxorubicin on the heart are still an area that warrants further investigation. Analysis of the literature data suggests that the mechanisms of doxorubicin's cardiotoxicity are multifactorial (Renu et al, 2018;Wenningmann et al, 2019) and include the impairment of mitochondrial energetics, increase of reactive oxygen species (ROS) leading to oxidative stress, cell necrosis and induction of pro-apoptotic signaling pathways (Chaudhari et al, 2017;Pecoraro et al, 2017;Delehanty et al, 2018).…”