Cisplatin compromises myocardial contractile function and mitochondrial ultrastructure: Role of endoplasmic reticulum stress

Abstract

1. Cisplatin is a potent chemotherapeutic agent with broad-spectrum antineoplastic activity against various types of tumours. However, a major factor limiting treatment with cisplatin is its acute and cumulative cardiotoxicity. The aim of the present study was to explore the effect of cisplatin on myocardial contractile function and the possible underlying cellular mechanisms. 2. C57 mice were treated with cisplatin (10 mg/kg per day, i.v.) or vehicle (0.9% NaCl) for 1 week and myocardial function was assessed using the Langendorff and cardiomyocyte edge-detection systems. Transmission electron microscopy, mitochondrial membrane potential, indices of endoplasmic reticulum (ER) stress and caspase 3 activity were evaluated. 3. Cisplatin-treated mice developed myocardial contractile dysfunction, as evidenced by a reduction in left ventricular developed pressure (LVDP) and the first derivative of LVDP (+/-dP/dt). Cisplatin treatment significantly prolonged time to 90% relengthening, depressed peak shortening, maximal velocity of shortening/relengthening (+/-dL/dt) and augmented the frequency-elicited depression in peak shortening. The JC-1 fluorescent assay demonstrated that cispatin-induced cardiac dysfunction was associated with mitochondrial membrane depolarization. Transmission electron microscopy revealed that cisplatin induces ultrastructural abnormalities of the mitochondria. Following cisplatin treatment, cardiomyocytes show activation of the ER stress response, increased caspase 3 activity and increased terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL) staining. 4. The data indicate that cisplatin is cardiotoxic and may lead to left ventricular dysfunction and depressed cardiomyocyte contraction associated with mitochondrial abnormalities, enhanced ER stress and apoptosis. This work should shed some light on the management of cisplatin-induced cardiac injury.

Effects of thymoquinone against cisplatin-induced cardiac injury in rats

“…Dolci et al 20 have classified the chemotherapy induced cardiotoxicity in two patterns: (1) Acute or subacute cardiotoxicity and (2) CP-induced cardiotoxicity is related to excessive oxidative stress and apoptosis 25 . Ma et al 6 have reported that depressed cardiomyocyte contraction and mitochondrial abnormalities, increased endoplasmic reticulum stress and associated apoptosis caused cardiac damage following CP treatment. Cardiomyocytes containing numerous mitochondria constitute an important site for CP accumulation and this condition eventually can lead to mitochondrial DNA damage 26 .…”

“…On the other hand, several experimental and clinical studies support the idea that the enhancement of oxidative stress may involve in this insult 6 .…”

Protective Effect of Pycnogenol^® on Cisplatin Induced-Cardiotoxicity in Rats

“…The cisplatinrelated cardiac dysfunction is due to the disruption of the mitochondrial membrane as well as the ultrastructural abnormalities seen in mitochondria. It was shown that, following CIS treatment, the endoplasmic reticulum stress response and apoptosis were increased in cardiomyocytes (15). CIS was shown to lead to renal injury by triggering the formation of mitochondrial reactive oxygen species in renal tubular cells (16).…”

Recurrent Complete Atrioventricular Block During Cisplatin Infusion: A Case Report

“…The sinus node may be influenced by several stimuli, and a hyperstimulation of the parasympathic as well as of the sympathic system may cause abnormal function of the sinus node and abnormal intraatrial or atrioventricular conduction. Cisplatin is cardiotoxic and may lead to left ventricular dysfunction and depressed cardiomyocyte contraction associated with mitochondrial abnormalities, enhanced endoplasmic reticulum stress and apoptosis [1,2].…”