Mechanisms of Disease: apoptosis in heart failure—seeing hope in death

Narula, Jagat; Haider, Nezam; Arbustini, Eloisa; Chandrashekhar, Y.

doi:10.1038/ncpcardio0710

Cited by 126 publications

(102 citation statements)

References 34 publications

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“…Importantly, the progression of heart failure, which is marked by a decline in cardiac function, has been associated with cardiomyocyte loss through activation of the apoptotic pathways [8][9][10]. This occurs through a signaling cascade, which includes cytochrome c release from the mitochondria, activation of caspases, protein, and DNA degradation [8,11,12]. Loss of myocytes represents an important component of cardiac remodeling and contributes to the transition from an adaptive myocardial condition to end-stage heart failure [13].…”

Section: Introductionmentioning

confidence: 99%

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

Vafiadaki

Papalouka

Arvanitis

et al. 2008

Pflugers Arch - Eur J Physiol

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Intracellular calcium is a major coordinator of numerous aspects of cellular physiology, including muscle contractility and cell survival. In cardiac muscle, aberrant Ca(2+) cycling has been implicated in a range of pathological conditions including cardiomyopathies and heart failure. The sarco(endo)plasmic reticulum Ca(2+) transport adenosine triphosphatase (SERCA2a) and its regulator phospholamban (PLN) have a central role in modulating Ca(2+) homeostasis and, therefore, cardiac function. Herein, we discuss the mechanisms through which SERCA2a and PLN control cardiomyocyte function in health and disease. Emphasis is placed on our newly identified PLN-binding partner HS-1-associated protein X-1 (HAX-1), which has an anti-apoptotic function and presents with numerous similarities to Bcl-2. Recent evidence indicates that proteins of the Bcl-2 family can influence ER Ca(2+) content, a critical determinant of cellular sensitivity to apoptosis. The discovery of the PLN/HAX-1 interaction therefore unveils an important new link between Ca(2+) homeostasis and cell survival, with significant therapeutic potential.

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Section: Introductionmentioning

confidence: 99%

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

Vafiadaki

Papalouka

Arvanitis

et al. 2008

Pflugers Arch - Eur J Physiol

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“…Caspase-3 activation during mammalian cell apoptosis is associated with phosphatidylserine expression on apoptotic cells (5). Annexin-A5 (AA5), which has a nanomolar affinity for binding to phosphatidylserine, has been used for the in vitro (6,7) and in vivo (8,9) detection of apoptosis.…”

mentioning

confidence: 99%

Annexin A5 Uptake in Ischemic Myocardium: Demonstration of Reversible Phosphatidylserine Externalization and Feasibility of Radionuclide Imaging

Kenis¹,

Zandbergen²,

Hofstra³

et al. 2010

J Nucl Med

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Ischemic insult to the myocardium is associated with cardiomyocyte apoptosis. Because apoptotic cell death is characterized by phosphatidylserine externalization on cell membrane and annexin-A5 (AA5) avidly binds to phosphatidylserine, we hypothesized that radiolabeled AA5 should be able to identify the regions of myocardial ischemia. Methods: Models of brief myocardial ischemia by the occlusion of the coronary artery for 10 min (I-10) and reperfusion for 180 min (R-180) for the detection of phosphatidylserine exteriorization using 99m Tc-labeled AA5 and g-imaging were produced in rabbits. 99m Tc-AA5 uptake after brief ischemia was compared with an I-40/R-180 infarct model. Histologic characterization of both myocardial necrosis and apoptosis was performed in ischemia and infarct models. Phosphatidylserine exteriorization was also studied in a mouse model, and the dynamics and kinetics of phosphatidylserine exposure were assessed using unlabeled recombinant AA5 and AA5 labeled with biotin, Oregon Green, or Alexa 568. Appropriate controls were established. Results: Phosphatidylserine exposure after ischemia in the rabbit heart could be detected by radionuclide imaging with 99m Tc-AA5. Pathologic characterization of the explanted rabbit hearts did not show apoptosis or necrosis. Homogenization and ultracentrifugation of the ischemic myocardial tissue from rabbit hearts recovered two thirds of the radiolabeled AA5 from the cytoplasmic compartment. Murine experiments demonstrated that the cardiomyocytes expressed phosphatidylserine on their cell surface after an ischemic insult of 5 min. Phosphatidylserine exposure occurred continuously for at least 6 h after solitary ischemic insult. AA5 targeted the exposed phosphatidylserine on cardiomyocytes; AA5 was internalized into cytoplasmic vesicles within 10-30 min. Twenty-four hours after ischemia, cardiomyocytes with internalized AA5 had restored phosphatidylserine asymmetry of the sarcolemma, and no detectable phosphatidylserine remained on the cell surface. The preadministration of a pan-caspase inhibitor, zVAD-fmk, prevented phosphatidylserine exposure after ischemia. Conclusions: After a single episode of ischemia, cardiomyocytes express phosphatidylserine, which is amenable to targeting by AA5, for at least 6 h. Phosphatidylserine exposure is transient and internalized in cytoplasmic vesicles after AA5 binding, indicating the reversibility of the apoptotic process.

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“…Moreover, it is also an important signaling molecule that induces some genes related to oxidative stress (Ji 1999). An oxidative-stress-induced inflammatory event leading to cellular or tissue injury is considered as a unifying mechanism of injury in many types of disease processes, such as renal, cardiovascular, neoplastic, and neurodegenerative diseases, and aging (Narula et al 2006;Onyango and Khan 2006;Wardle 2005).…”

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confidence: 99%

Heat-shock response protects peripheral blood mononuclear cells (PBMCs) from hydrogen peroxide-induced mitochondrial disturbance

Chiu

Tsao

Yang

2009

Cell Stress and Chaperones

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The present study was designed to investigate ex vivo the protective mechanisms of heat-shock response against H 2 O 2 -induced oxidative stress in peripheral blood mononuclear cells (PBMCs) of rats. Twenty-four hours later, heat-shock treatment was executed in vivo; rat PBMCs were collected and treated with H 2 O 2 . The accumulation of reactive oxygen species and the mitochondrial membrane potential were evaluated by intracellular fluorescent dHE and JC-1 dye staining, respectively, and expression of HSP72 and cytochrome c was detected by Western blot analysis. Cellular apoptosis was assayed by TUNEL staining and double staining of Annexin V and PI. The results showed that H 2 O 2 -induced oxidative stress leads to intracellular superoxide accumulation and collapse of the mitochondrial membrane potential in rat PBMCs. Moreover, cellular apoptosis was detected after H 2 O 2 treatment, and the release of mitochondrial cytochrome c from mitochondria to cytosol was significantly enhanced. Heat-shock pretreatment decreases the accumulation of intracellular superoxide in PBMCs during H 2 O 2 -induced oxidative stress. Moreover, heat-shock treatment prevents the collapse of the mitochondrial membrane potential and cytochrome c release from mitochondria during H 2 O 2 -induced oxidative stress. In conclusion, mitochondria are critical organelles of the protective effects of heat-shock treatment. Cellular apoptosis during H 2 O 2 -induced oxidative stress is decreased by heat-shock treatment through a decrease in superoxide induction and preservation of the mitochondrial membrane potential.

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Mechanisms of Disease: apoptosis in heart failure—seeing hope in death

Cited by 126 publications

References 34 publications

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

The role of SERCA2a/PLN complex, Ca2+ homeostasis, and anti-apoptotic proteins in determining cell fate

Annexin A5 Uptake in Ischemic Myocardium: Demonstration of Reversible Phosphatidylserine Externalization and Feasibility of Radionuclide Imaging

Heat-shock response protects peripheral blood mononuclear cells (PBMCs) from hydrogen peroxide-induced mitochondrial disturbance

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