Preventive Effect of Canstatin against Ventricular Arrhythmia Induced by Ischemia/Reperfusion Injury: A Pilot Study

Abstract

Ventricular arrhythmia induced by ischemia/reperfusion (I/R) injury is a clinical problem in reperfusion therapies for acute myocardial infarction. Ca2+ overload through reactive oxygen species (ROS) production is a major cause for I/R-induced arrhythmia. We previously demonstrated that canstatin, a C-terminal fragment of type IV collagen α2 chain, regulated Ca2+ handling in rat heart. In this study, we aimed to clarify the effects of canstatin on I/R-induced ventricular arrhythmia in rats. Male Wistar rats were subjected to I/R injury by ligating the left anterior descending artery followed by reperfusion. Ventricular arrhythmia (ventricular tachycardia and ventricular fibrillation) was recorded by electrocardiogram. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and ROS production in neonatal rat cardiomyocytes (NRCMs) stimulated with oxygen glucose deprivation/reperfusion (OGD/R) were measured by lucigenin assay and 2′,7′-dichlorodihydrofluorescein diacetate staining, respectively. The H2O2-induced intracellular Ca2+ ([Ca2+]i) rise in NRCMs was measured by a fluorescent Ca2+ indicator. Canstatin (20 µg/kg) inhibited I/R-induced ventricular arrhythmia in rats. Canstatin (250 ng/mL) inhibited OGD/R-induced NOX activation and ROS production and suppressed the H2O2-induced [Ca2+]i rise in NRCMs. We for the first time demonstrated that canstatin exerts a preventive effect against I/R-induced ventricular arrhythmia, perhaps in part through the suppression of ROS production and the subsequent [Ca2+]i rise.

Multi-omics profiling identifies microglial Annexin A2 as a key mediator of NF-κB pro-inflammatory signaling in ischemic reperfusion injury

“…We also found Anxa2 translocated to the membrane in microglial cells in response to OGD/R. Several studies have suggested that I/R and OGD/R exposure triggered the elevation of intracellular Ca 2+ concentration ( 43 , 99 ). While Anxa2 is a member of the family of Ca 2+ -dependent anionic phospholipid-binding proteins, Anxa2 can bind cell surface receptor S100a10, increasing the Ca 2+ sensitivity of Anxa2 and leading to binding membranes ( 100 ).…”

“…The OGD/R model has been described previously ( 43 ). BV2 cells were plated in an anaerobic incubator with 5% CO 2 and 95% atmospheric air overnight.…”

Autocrine role of senescent cardiac fibroblasts-derived extracellular vesicles

“…NRCFs and NRCMs were isolated from neonatal Wistar rats as described previously [ 28 , 29 ]. The hearts were harvested from neonatal Wistar rats (1–3-day-old) and transferred immediately into the dish containing phosphate buffered saline (PBS) with 20 mM 2,3-butanedione monoxime (BDM) on ice.…”

The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen

“…Arresten has been shown to reduce the invasiveness of squamous cell carcinoma in mice [ 177 ]. Canstatin has also been shown to prevent ventricular arrhythmia in an ischemia/reperfusion rat model, partly by inhibiting the production of reactive oxygen species and the elevation of intracellular Ca 2+ levels [ 178 ]. Additionally, canstatin also protected the rat right ventricle from fibrotic remodeling induced by experimental pulmonary arterial hypertension, possibly by interfering with Ca 2+ /calcineurin pathways [ 179 ].…”