Emerging roles of caspase-3 in apoptosis

Porter, Alan G.; Jänicke, Reiner U.

doi:10.1038/sj.cdd.4400476

Cited by 3,321 publications

(2,224 citation statements)

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“…The severity of cardiac remodeling directly correlates with the rate and duration of pacing in pacing HF models,14 whereas it has been shown that cardiac apoptosis occurs rapidly after MI, and sustained apoptosis is associated with the extent of cardiac remodeling in HF models after MI 23, 24. To evaluate the extent of cardiac apoptosis in the ischemic HF model, we evaluated the protein expression of cleaved caspase 3 and caspase 3, which are essential for the apoptotic process 25. As a result, LAA in ischemic HF rabbits had a significantly higher activation of caspase 3 compared with that in control and HF‐RDN rabbits.…”

Section: Discussionmentioning

confidence: 99%

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure

Yamada

Fong

Hsiao

et al. 2018

JAHA

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BackgroundMyocardial infarction increases the risk of heart failure (HF) and atrial fibrillation. Renal denervation (RDN) might suppress the development of atrial remodeling. This study aimed to elucidate the molecular mechanism of RDN in the suppression of atrial fibrillation in a HF model after myocardial infarction.Methods and Results HF rabbits were created 4 weeks after coronary ligation. Rabbits were classified into 3 groups: normal control (n=10), HF (n=10), and HF‐RDN (n=6). Surgical and chemical RDN were approached through midabdominal incisions in HF‐RDN. Left anterior descending coronary artery in HF and HF‐RDN was ligated to create myocardial infarction. After electrophysiological study, the rabbits were euthanized and the left atrial appendage was harvested for real‐time polymerase chain reaction analysis and Trichrome stain. Left atrial dimension and left ventricular mass were smaller in HF‐RDN by echocardiography compared with HF. Attenuated atrial fibrosis and tyrosine hydroxylase levels were observed in HF‐RDN compared with HF. The mRNA expressions of Cav1.2, Nav1.5, Kir2.1, KvLQT1, phosphoinositide 3‐kinase, AKT, and endothelial nitric oxide synthase in HF‐RDN were significantly higher compared with HF. The effective refractory period and action potential duration of HF‐RDN were significantly shorter compared with HF. Decreased atrial fibrillation inducibility was noted in HF‐RDN compared with HF (50% versus 100%, P<0.05).Conclusions RDN reversed atrial electrical and structural remodeling, and suppressed the atrial fibrillation inducibility in an ischemic HF model. The beneficial effect of RDN may be related to prevention of the downregulation of the phosphoinositide 3‐kinase/AKT/endothelial nitric oxide synthase signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Impact of Renal Denervation on Atrial Arrhythmogenic Substrate in Ischemic Model of Heart Failure

Yamada

Fong

Hsiao

et al. 2018

JAHA

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“…Indeed, we can suppose that cytochrome-c associates with Apaf-1 in the presence of dATP or ATP and induces its oligomerization [Hengartner, 2000]. Furthermore, the oligomeric Apaf-1 complex would recognize the inactive procaspase-9, forming the "apoptosome" [Porter and Janicke, 1999], which in turn induce autocatalytic processing of procaspase-9. Subsequently, the mature caspase-9 would activate its primary downstream target, procaspase-3, which can cleave some nuclear proteins such as PARP, leading to a typical apoptotic DNA fragmentation in multiples of 180-200 bp [Green and Kroemer, 1998].…”

Section: Discussionmentioning

confidence: 99%

“…All caspases are synthesized as enzymatically inert zymogens and are activated by autocatalytic cleavage or by activation of other caspases. Among the various caspases, caspase-9 and caspase-3 appear to be important in apoptosis [Porter and Janicke, 1999;Kuida, 2000]. Activation of Bax and Bak results in the release of cytochrome-c from mitochondria Wei et al, 2001], which binds to Apaf-1 and promotes activation of procaspase-9, forming the apoptosome and resulting in caspase-9 activation [Li et al, 1997;Green and Reed, 1998].…”

Section: Introductionmentioning

confidence: 99%

“…The activated caspase-9 cleaves downstream caspases such as caspase-3 and caspase-6. Effector caspases like caspase-3, 6, and 7 are responsible for initiating the events that lead to the hallmarks of apoptosis, including chromatin condensation, DNA fragmentation, cleavage of poly (ADPribose) polymerase (PARP), and formation of apoptotic bodies [Porter and Janicke, 1999].…”

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confidence: 99%

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Mitochondrial mechanism of microvascular endothelial cells apoptosis in hyperhomocysteinemia

Tyagi

Ovechkin

Lominadze

et al. 2006

J of Cellular Biochemistry

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An elevated level of homocysteine (Hcy) limits the growth and induces apoptosis. However, the mechanism of Hcy-induced programmed cell death in endothelial cells is largely unknown. We hypothesize that Hcy induces intracellular reactive oxygen species (ROS) production that leads to the loss of transmembrane mitochondrial potential (Δψ m ) accompanied by the release of cytochrome-c from mitochondria. Cytochrome-c release contributes to caspase activation, such as caspase-9, caspase-6, and caspase-3, which results in the degradation of numerous nuclear proteins including poly (ADP-ribose) polymerase (PARP), which subsequently leads to the internucleosomal cleavage of DNA, resulting cell death. In this study, rat heart microvascular endothelial cells (MVEC) were treated with different doses of Hcy at different time intervals. Apoptosis was measured by DNA laddering and transferase-mediated dUTP nick-end labeling (TUNEL) assay. ROS production and MP were determined using florescent probes (2,7-dichlorofluorescein (DCFH-DA) and 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzamidazolocarbocyanin iodide (JC-1), respectively, by confocal microscopy. Differential gene expression for apoptosis was analyzed by cDNA array. The results showed that Hcy-mediated ROS production preceded the loss of MP, the release of cytochrome-c, and the activation of caspase-9 and -3. Moreover the Hcy treatment resulted in a decrease in Bcl 2 /Bax ratio, evaluated by mRNA levels. Caspase-9 and -3 were activated, causing cleavage of PARP, a hallmark of apoptosis and internucleosomal DNA fragmentation. The cytotoxic effect of Hcy was blocked by using small interfering RNA (siRNA)-mediated suppression of caspase-9 in MVEC. Suppressing the activation of caspase-9 inhibited the activation of caspase -3 and enhanced the cell viability and MP. Our data suggested that Hcy-mediated ROS production promotes endothelial cell death in part by disturbing MP, which results in subsequent release of cytochrome-c and activation of caspase-9 and 3, leading to cell death. KeywordsPARP; cytochrome-c; reactive oxygen species; siRNA; cardiac microvascular endothelial cells; oxidative stress; mitochondrial membrane potential; siRNA; cDNA array; TUNEL; Bax; Bcl 2 ; caspase Hyperhomocysteinemia is an independent risk factor for cardiovascular disease, stroke, and peripheral vascular disease [Jacobsen, 1998;Hankey and Eikelboom, 1999;Fallon et al., 2001;Suhara et al., 2004] [Tsai et al., 1994].Hcy is a thiol-containing amino acid formed during the intracellular demethylation of methionine and causes multifold effects through the reactivity of its sufhydryl group. Increase in levels of Hcy impairs cellular function and leads to loss of endothelial antithrombotic function, lipid peroxidation, impairment of platelet aggregation, enhanced oxidative stress, and apoptosis (programmed cell death) [Blom et al., 1995;Tawakol et al., 1997;Carsten and Kenneth, 2004]. These unfavorable vascular effects of Hcy are a result of the generation of reactive oxygen species (ROS) [...

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“…Based on their order in cell death pathways, caspases can be divided into initiator (caspase-2, -8, -9, and -10) and effector (caspase-3, -6, and -7) caspases. Among them, caspase-3, a member of the latter group, is absolutely crucial for apoptosis induction, as this enzyme is not only activated downstream of both the extrinsic and intrinsic death pathway, it is also responsible for the cleavage of the majority of substrates known so far [1,5]. More importantly, with the proteolysis of discrete substrates, caspase-3 evokes some of the typical morphological and biochemical alterations associated with apoptosis.…”

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confidence: 99%