MAPK Superfamily Plays an Important Role in Daunomycin-Induced Apoptosis of Cardiac Myocytes

Zhu, Weidong; Zou, Yunzeng; Aikawa, Ryuichi; Harada, Koichiro; Kudoh, Sumiyo; Uozumi, Hiroki; Hayashi, Doubun; Gu, Yuchun; Yamazaki, Tsutomu; Nagai, Ryozo; Yazaki, Yoshio; Komuro, Issei

doi:10.1161/01.cir.100.20.2100

Cited by 148 publications

(115 citation statements)

References 30 publications

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“…␤ 1 -AR may stimulate apoptosis via a PKA-calcium-dependent mechanism (5), and oppose apoptosis via the activation of p38 kinase. Simultaneous activation of apoptotic and antiapoptotic pathways in cardiac myocytes has been observed with daunomycin (43). Finally, it is possible that the apparent ability of both ␤ 1 -and ␤ 2 -AR subtypes to activate p38 kinase may reflect differential activation of p38 kinase isoforms, which may exert opposing effects on apoptosis in cardiac myocytes (21).…”

Section: Discussionmentioning

confidence: 98%

p38 Mitogen-activated Protein Kinase Pathway Protects Adult Rat Ventricular Myocytes against β-Adrenergic Receptor-stimulated Apoptosis

Communal

Colucci

Singh

2000

Journal of Biological Chemistry

149

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We have shown that stimulation of ␤-adrenergic receptors (␤-AR) by norepinephrine (NE) increases apoptosis in adult rat ventricular myocytes (ARVMs) via a cAMP-dependent mechanism that is antagonized by activation of G i protein. The family of mitogen-activated protein kinases (MAPKs) is involved in the regulation of cardiac myocyte growth and apoptosis. Here we show that ␤-AR stimulation activates p38 kinase, c-jun N-terminal kinases (JNKs), and extracellular signal-regulated kinase (ERK1/2) in ARVMs. Inhibition of p38 kinase with SB-202190 (10 M) potentiated ␤-ARstimulated apoptosis as measured by flow cytometry and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) staining. SB-202190 at this concentration specifically blocked ␤-AR-stimulated activation of p38 kinase and its downstream substrate MAPK-activated protein kinase-2 (MAPKAPK2). Pertussis toxin, an inhibitor of G i /G o proteins, blocked the activation of p38 kinase and potentiated ␤-AR-stimulated apoptosis. Activation of G i protein with the muscarinic receptor agonist carbachol protected against ␤-ARstimulated apoptosis. Carbachol also activated p38 kinase, and the protective effect of carbachol was abolished by SB-202190. PD-98059 (10 M), an inhibitor of ERK1/2 pathway, blocked ␤-AR-stimulated activation of ERK1/2 but had no effect on apoptosis. These data suggest that 1) ␤-AR stimulation activates p38 kinase, JNKs, and ERK1/2; 2) activation of p38 kinase plays a protective role in ␤-AR-stimulated apoptosis in cardiac myocytes; and 3) the protective effects of G i are mediated via the activation of p38 kinase.Apoptosis occurs in the myocardium of patients with endstage heart failure and myocardial infarction and in animal models of myocardial hypertrophy and failure (1-4). We demonstrated that stimulation of ␤-adrenergic receptors (␤-AR) 1 induces apoptosis in adult rat ventricular myocytes (ARVMs) in vitro (5). This effect was mimicked by the adenylyl cyclase stimulator forskolin and blocked by inhibition of protein kinase A, suggesting a role for cAMP in ␤-AR-stimulated apoptosis in ARVMs. Likewise, showed that ␤-AR stimulation increases apoptosis in a cAMP-protein kinase Adependent manner in neonatal rat cardiac myocytes. We further demonstrated that activation of G i inhibits ␤-AR-stimulated apoptosis in ARVMs (7).Mitogen-activated protein kinases (MAPKs), a large family of serine-threonine kinases, have important functions as mediators of signal transduction and are activated by a variety extracellular stimuli (8 -10). Three subgroups of MAPKs have clearly been identified: the extracellular signal-regulated kinase (ERK1/2), the p38 kinase, and the c-jun N-terminal kinases (JNKs). ERK1/2 respond to mitogenic stimuli, whereas p38 kinase and JNKs respond predominantly to cellular stresses or inflammatory cytokines (9, 10). Recently, heterotrimeric G proteins have also been shown to activate various members of the MAPKs family (11-15). The ␤ 2 -AR-stimulated dissociation of the ␤␥-subunit of G i activates ERK1/2 in HEK293 ...

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Section: Discussionmentioning

confidence: 98%

p38 Mitogen-activated Protein Kinase Pathway Protects Adult Rat Ventricular Myocytes against β-Adrenergic Receptor-stimulated Apoptosis

Communal

Colucci

Singh

2000

Journal of Biological Chemistry

149

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“…These results indicate that Csx/Nkx2-5 protects hearts from the cardiotoxic effects of DOX. Because we have previously demonstrated that DOX induces apoptosis in cultured cardiomyocytes (22), we further examined cardiomyocyte apoptosis in these mice after DOX injection. TUNEL and immunohistochemical analysis using anti-active caspase-3 antibody revealed that there were more apoptotic cells in the order of DN-TG mice, non-TG mice, and WT-TG mice.…”

Section: Discussionmentioning

confidence: 99%

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

Toko¹,

Zhu²,

Takimoto³

et al. 2002

Journal of Biological Chemistry

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Csx/Nkx2-5, which is essential for cardiac development of the embryo, is abundantly expressed in the adult heart. We here examined the role of Csx/Nkx2-5 in the adult heart using two kinds of transgenic mice. Transgenic mice that overexpress a dominant negative mutant of Csx/Nkx2-5 (DN-TG mice) showed degeneration of cardiac myocytes and impairment of cardiac function. Doxorubicin induced more marked cardiac dysfunction in DN-TG mice and less in transgenic mice that overexpress wild type Csx/Nkx2-5 (WT-TG mice) compared with non-transgenic mice. Doxorubicin induced cardiomyocyte apoptosis, and the number of apoptotic cardiomyocytes was high in the order of DN-TG mice, non-transgenic mice, and WT-TG mice. Overexpression of the dominant negative mutant of Csx/Nkx2-5 induced apoptosis in cultured cardiomyocytes, while expression of wild type Csx/Nkx2-5 protected cardiomyocytes from doxorubicin-induced apoptotic death. These results suggest that Csx/Nkx2-5 plays a critical role in maintaining highly differentiated cardiac phenotype and in protecting the heart from stresses including doxorubicin.The cardiac homeobox gene Csx/Nkx2-5 starts to be expressed at embryonic day 7.5 in the heart primordia of mice (1, 2), and targeted disruption of murine Csx/Nkx2-5 results in embryonic lethality (3). Many mutations in human Csx/Nkx2-5 have been reported to cause a variety of congenital heart diseases and atrioventricular conduction delay (4, 5). These observations indicate that Csx/Nkx2-5 plays a critical role in cardiac morphogenesis and contributes to diverse cardiac developmental pathways at the embryonic stage.Knockout experiments have suggested that many genes such as Hand1, myocyte enhancer factor-2, atrial natriuretic peptide (ANP), 1 brain natriuretic peptide (BNP), cardiac ␣-actin, cardiac ankyrin repeat protein (CARP), N-myc, and MSX2 are genetically located downstream of Csx/Nkx2-5 at the embryonic stage (2, 6 -8). Although Csx/Nkx2-5 continues to be expressed in the adult heart (1, 2), the function of Csx/Nkx2-5 in the later stage of development is unknown because of embryonic lethality of null mutant mice (3, 8). In our recently generated transgenic mice that overexpress human Csx/Nkx2-5 (WT-TG mice), mRNA levels of many cardiac genes such as ANP, BNP, CARP, and sarcoplasmic reticulum calcium ATPase 2 (SERCA2) genes were up-regulated (9). These results suggest that Csx/Nkx2-5 regulates expression of cardiac-specific genes also in the adult heart. However, because there was no difference in phenotype between WT-TG and non-transgenic (non-TG) mice (9), the significance of these gene up-regulations remains unknown. Csx/Nkx2-5 itself is also differentially regulated by different stimuli. In response to hypertrophic stimuli such as isoproterenol, phenylephrine, and pressure overload, Csx/Nkx2-5 is upregulated (10, 11), whereas it is down-regulated by treatment with doxorubicin (DOX) (12). These results suggest that Csx/ Nkx2-5 has certain roles in the adult heart. In this study, we generated transgenic mice that over...

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“…2,8,9 To determine whether the pro-apoptotic effects of doxorubicin are regulated through activation of ZAK, we examined the cleavage of poly (ADP-ribose) polymerase (PARP) (from 116 kDa to 89 kDa) and caspase-3 (from procaspase to p20/p19 and p17 subunits), which are frequently employed as indicators of apoptosis. Knockdown mechanisms.…”

Section: Doxorubicinmentioning

confidence: 99%

“…Inhibitors of p38 MAPK have been effective in blocking apoptosis of cardiomyocytes following treatment by doxorubicin or daunorubicin, a related anthracycline. 8,9 Inhibitors of p38 MAPK reduce the proinflammatory actions of doxorubicin in macrophages but of ZAK suppressed the doxorubicin-induced cleavage of both PARP and caspase-3 in HaCaT cells (Fig. 1a).…”

Section: Introductionmentioning

confidence: 96%

“…Doxorubicin is known to induce the activation of SAPKs in a number of normal cell types, including hepatocytes, 6 primary mouse macrophages 7 and cardiomyocytes. 8,9 Inhibitors of p38 MAPK and JNK have been employed to determine whether activation of SAPKs contributes either to the efficacy or to the undesirable side effects of doxorubicin. Inhibitors of p38 MAPK have been effective in blocking apoptosis of cardiomyocytes following treatment by doxorubicin or daunorubicin, a related anthracycline.…”

Section: Introductionmentioning

confidence: 99%

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ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

Sauter

Magun

Iordanov

et al. 2010

Cancer Biology & Therapy

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MAPK Superfamily Plays an Important Role in Daunomycin-Induced Apoptosis of Cardiac Myocytes

Cited by 148 publications

References 30 publications

p38 Mitogen-activated Protein Kinase Pathway Protects Adult Rat Ventricular Myocytes against β-Adrenergic Receptor-stimulated Apoptosis

p38 Mitogen-activated Protein Kinase Pathway Protects Adult Rat Ventricular Myocytes against β-Adrenergic Receptor-stimulated Apoptosis

Csx/Nkx2-5 Is Required for Homeostasis and Survival of Cardiac Myocytes in the Adult Heart

ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells

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