Regulatory volume decrease in cardiomyocytes is modulated by calcium influx and reactive oxygen species

AbstractWe investigated the role of Ca2+ in generating reactive oxygen species (ROS) induced by hyposmotic stress (Hypo) and its relationship to regulatory volume decrease (RVD) in cardiomyocytes. Hypo-induced increases in cytoplasmic and mitochondrial Ca2+. Nifedipine (Nife) inhibited both Hypo-induced Ca2+ and ROS increases. Overexpression of catalase (CAT) induced RVD and a decrease in Hypo-induced blebs. Nife prevented CAT-dependent RVD activation. These results show a dual role of Hypo-induced Ca2+ influx in the control of cardiomyocyte viability. Hypo-induced an intracellular Ca2+ increase which activated RVD and inhibited necrotic blebbing thus favoring cell survival, while simultaneously increasing ROS generation, which in turn inhibited RVD and induced necrosis

Mitochondria, myocardial remodeling, and cardiovascular disease

The process of muscle remodeling lies at the core of most cardiovascular diseases. Cardiac adaptation to pressure or volume overload is associated with a complex molecular change in cardiomyocytes which leads to anatomic remodeling of the heart muscle. Although adaptive at its beginnings, the sustained cardiac hypertrophic remodeling almost unavoidably ends in progressive muscle dysfunction, heart failure and ultimately death. One of the features of cardiac remodeling is a progressive impairment in mitochondrial function. The heart has the highest oxygen uptake in the human body and accordingly it has a large number of mitochondria, which form a complex network under constant remodeling in order to sustain the high metabolic rate of cardiac cells and serve as Ca2+ buffers acting together with the endoplasmic reticulum (ER). However, this high dependence on mitochondrial metabolism has its costs: when oxygen supply is threatened, high leak of electrons from the electron transport chain leads to oxidative stress and mitochondrial failure. These three aspects of mitochondrial function (Reactive oxygen species signaling, Ca2+ handling and mitochondrial dynamics) are critical for normal muscle homeostasis. In this article, we will review the latest evidence linking mitochondrial morphology and function with the process of myocardial remodeling and cardiovascular disease

Hyperosmotic stress activates p65/RelB NF kappa B in cultured cardiomyocytes with dichotomic actions on caspase activation and cell death

NF kappa B is a participant in the process whereby cells adapt to stress. We have evaluated the activation of NF kappa B pathway by hyperosmotic stress in cultured cardiomyocytes and its role in the activation of caspase and cell death. Exposure of cultured rat cardiomyocytes to hyperosmotic conditions induced phosphorylation of IKK alpha/beta as well as degradation of I kappa B alpha. All five members of the NF kappa B family were identified in cardiomyocytes. Analysis of the subcellular distribution of NF kappa B isoforms in response to hyperosmotic stress showed parallel migration of p65 and ReIB from the cytosol to the nucleus. Measurement of the binding of NF kappa B to the consensus DNA kappa B-site binding by EMSA revealed an oscillatory profile with maximum binding 1, 2 and 6 h after initiation of the hyperosmotic stress. Supershift analysis revealed that p65 and ReIB (but not p50, p52 or cReI) were involved in the binding of NF kappa B to DNA. Hyperosmotic stress also resulted in activation of the NF kappa B-lux reporter gene, transient activation of caspases 9 and 3 and phosphatidylserine externalization. The effect on cell viability was not prevented by ZVAD (a general caspase inhibitor). Blockade of NF kappa B with AdI kappa B alpha, an I kappa B alpha dominant negative overexpressing adenovirus, prevented activation of caspase 9 (more than that caspase 3) but did not affect cell death in hyperosmotically stressed cardiomyocytes. We conclude that hyperosmotic stress activates p65 and ReIB NF kappa B isoforms and NF kappa B mediates caspase 9 activation in cardiomyocytes. However cell death triggered by hyperosmotic stress was caspase- and NF kappa B-independent

Hyperosmotic stress activates p65/RelB NFκB in cultured cardiomyocytes with dichotomic actions on caspase activation and cell death

NFκB is a participant in the process whereby cells adapt to stress. We have evaluated the activation of NFκB pathway by hyperosmotic stress in cultured cardiomyocytes and its role in the activation of caspase and cell death. Exposure of cultured rat cardiomyocytes to hyperosmotic conditions induced phosphorylation of IKKα/β as well as degradation of IκBα. All five members of the NFκB family were identified in cardiomyocytes. Analysis of the subcellular distribution of NFκB isoforms in response to hyperosmotic stress showed parallel migration of p65 and RelB from the cytosol to the nucleus. Measurement of the binding of NFκB to the consensus DNA κB-site binding by EMSA revealed an oscillatory profile with maximum binding 1, 2 and 6 h after initiation of the hyperosmotic stress. Supershift analysis revealed that p65 and RelB (but not p50, p52 or cRel) were involved in the binding of NFκB to DNA. Hyperosmotic stress also resulted in activation of the NFκB-lux reporter gene, transient act

Systemic oxidative stress and endothelial dysfunction is associated with an attenuated acute vascular response to inhaled prostanoid in pulmonary artery hypertension patients

Background: Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients. Methods: Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography. Results: PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P <.01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 μM, P <.01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P =.02, respectively) and decreased eSOD activity (235 ± 23 vs. 461