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Arsenic trioxide triggered calcium homeostasis imbalance and induced endoplasmic reticulum stress-mediated apoptosis in adult rat ventricular myocytes.

ABSTRACT: Arsenic trioxide (ATO) is a potent anticancer drug agent but its clinical use is often limited by severe cardiotoxicity. However, its exact mechanism remains poorly understood. In this study, we simultaneously explored the direct effect of ATO on cardiac contraction in adult rat ventricular myocytes and its effects on Ca2+ transient in real time by using an IonOptix MyoCam system. The results showed that ATO increased the amplitude of sarcomere shortening, the maximal velocity of relengthening and shortening (-dL/dtmax and +dL/dtmax), time-to-90% relengthening (TR90), and time-to-peak shortening (TPS), resulting in abnormal cardiomyocyte contraction. Meanwhile, ATO markedly increased the resting Ca2+ ratio, amplitude/resting calcium, the maximal velocity of Ca2+ shortening and relaxation (+d[Ca2+]/dtmax and -d[Ca2+]/dtmax), time-to-50% peak [Ca2+] i and the decay rate of [Ca2+] i transients, suggesting that ATO leads to intracellular imbalance of calcium homeostasis. ATO also inhibited sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) activity in a time-dependent manner and activated the endoplasmic reticulum (ER) stress reaction. These results revealed that ATO dramatically aggravates Ca2+ overload and promotes ER stress, eventually causing abnormal cardiomyocyte contraction in a dose-dependent and time-dependent manner.

SUBMITTER: Zhang JY

PROVIDER: S-EPMC6062323 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Arsenic trioxide triggered calcium homeostasis imbalance and induced endoplasmic reticulum stress-mediated apoptosis in adult rat ventricular myocytes.

Zhang Jing-Yi JY Sun Gui-Bo GB Wang Min M Liao Ping P Du Yu-Yang YY Yang Ke K Sun Xiao-Bo XB

Toxicology research 20160208 2

Arsenic trioxide (ATO) is a potent anticancer drug agent but its clinical use is often limited by severe cardiotoxicity. However, its exact mechanism remains poorly understood. In this study, we simultaneously explored the direct effect of ATO on cardiac contraction in adult rat ventricular myocytes and its effects on Ca<sup>2+</sup> transient in real time by using an IonOptix MyoCam system. The results showed that ATO increased the amplitude of sarcomere shortening, the maximal velocity of rele ...[more]

PMID: 30090381

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Project description:Endoplasmic reticulum (ER) stress has been demonstrated to play important roles in the pathogenesis of various cardiovascular diseases. The ER stress pathway is therefore a promising therapeutic target in cardiovascular disease. Although Panax notoginseng saponins (PNS) are one of the patent medicines that are traditionally used to treat cardiovascular disorders, their effects on ER stress in cardiac myocytes remain unexploited so far. This study investigates the effects of PNS on ER stress and its associated cell apoptosis along with the related mechanism in cardiac myocytes. PNS compounds were identified via high-performance liquid chromatograph (HPLC) assay. PNS-pretreated H9c2 cells, HL-1 cells, and primary cultured neonatal rat cardiomyocytes were stimulated with thapsigargin (TG) to induce ER stress response and apoptosis. ER stress response was tested by immunofluorescence or immunoblot of the ER protein chaperones-calnexin, binding immunoglobulin protein (BiP) and the C/EBP homologous protein (CHOP). Cell viability was tested by methyl thiazolyl tetrazolium (MTT) assay. Cell apoptosis was detected by immunoblot of Cleaved caspase-3 and flow cytometry analysis of Annexin V/propidium iodide (PI) staining. Cytosolic, mitochondrial, and ER calcium dynamics were investigated by calcium imaging. Moreover, a ryanodine receptor type-2 (RyR2) overexpression stable cell line was generated to verify the mechanism of RyR2 involved in PNS in the inhibition of ER stress and cell apoptosis. We demonstrate here that PNS protected cardiac myocytes from ER stress response and associated cell death in a concentration-dependent manner. Importantly, PNS reduced the elevation of cytosolic calcium, mitochondria calcium, as well as ER calcium in response to either TG or histamine treatment. PNS protection in ER stress was regulated by RyR2 expression. In summary, PNS protection against TG-induced ER stress response and its associated cell apoptosis in cardiac myocytes is calcium dependent. Through the regulation of ER calcium release mediated by RyR2, a novel mechanism for PNS in the prevention of cardiovascular diseases is thereby identified.

Dataset Information

Arsenic trioxide triggered calcium homeostasis imbalance and induced endoplasmic reticulum stress-mediated apoptosis in adult rat ventricular myocytes.

Publications

Arsenic trioxide triggered calcium homeostasis imbalance and induced endoplasmic reticulum stress-mediated apoptosis in adult rat ventricular myocytes.

Similar Datasets

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