The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model

Date, Motoo; Morita, Takashi; Yamashita, Nobushige; Nishida, Keiya; Yamaguchi, Osamu; Higuchi, Yoshiharu; Hirotani, Shinichi; Matsumura, Yasushi; Hori, Masatsugu; Tada, Michihiko; Otsu, Kinya

doi:10.1016/s0735-1097(01)01826-5

Cited by 142 publications

(114 citation statements)

References 19 publications

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“…9 In an in vivo murine model of pressure overload, we were able to show that pressure overload-induced oxidative stress in hearts and the resultant cardiac hypertrophy were attenuated by treatment with the antioxidant mercaptopropinonyl glycine. 11 However, for clinical use, an antioxidant with high accessibility to tissue or relatively slow clearance is needed. Edaravone was proven to have an inhibitory effect on a water-soluble and a lipid-soluble peroxyl radical-induced peroxidation system and to have sufficient accessibility to tissue, including hearts, so that it can effectively scavenge ROS in heart.…”

Section: Discussionmentioning

confidence: 99%

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The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Tsujimoto

Hikoso²,

Yamaguchi³

et al. 2005

Hypertension

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Abstract-The free radical scavenger 3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone) is used to treat patients with ischemic brain damage. We and others reported previously that in vitro and in vivo reactive oxygen species (ROS) act as second messengers to develop cardiac hypertrophy. In this study, we used an in vivo murine model of pressure overload-induced cardiac hypertrophy to examine the effects of edaravone on left ventricular hypertrophy. The animals were subjected to the transverse thoracic aorta constriction, and edaravone (10 mg/kg) was infused intraperitoneally twice daily. Seven days after the operation, we observed a significant increase in ROS production in hearts, which was eliminated by the treatment with edaravone. Pressure-overloaded hearts showed a significant increase in left ventricular weight/body weight ratio and the expression level of atrial natriuretic factor mRNA, which were attenuated by edaravone. It also reduced perivascular and intermuscular fibrosis and inhibited pressure overload-induced activation of apoptosis signal-regulating kinase 1 (ASK1) and its downstream kinases of c-Jun N-terminal protein kinase and p38 mitogen-activated protein kinase. Edaravone attenuated the hypertrophic response even when the treatment was started after the onset of cardiac hypertrophic response. These findings indicate that edaravone significantly attenuates pressure overload-induced cardiac hypertrophy mediated through its antioxidative function and subsequent inhibition of ASK1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

“…9,10 Similar results have been obtained with in vivo study. 11 Apoptosis signal-regulating kinase 1 (ASK1) is an ROSsensitive mitogen-activated protein (MAP) kinase kinase kinase that activates the c-Jun N-terminal protein kinase (JNK) and p38 MAP kinase. 12 ASK1 is associated with thioredoxin as an inactive form in nonstressed cells.…”

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confidence: 99%

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Tsujimoto

Hikoso²,

Yamaguchi³

et al. 2005

Hypertension

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“…Previous reports demonstrated that antioxidants attenuate pressure-overload cardiac hypertrophy. 19 Transgenic cardiac overexpression of thioredoxin decreases the myocardial infarct size after ischemia/reperfusion injury 20 and protects against adriamycininduced cardiotoxicity by reducing oxidative stress. 21 Therefore, thioredoxin may play a pivotal role in the myocardial defense against oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity

et al. 2004

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Background— Although cellular redox balance plays an important role in mechanically induced cardiac hypertrophy, the mechanisms of regulation are incompletely defined. Because thioredoxin is a major intracellular antioxidant and can also regulate redox-dependent transcription, we explored the role of thioredoxin activity in mechanically overloaded cardiomyocytes in vitro and in vivo. Methods and Results— Overexpression of thioredoxin induced protein synthesis in cardiomyocytes (127±5% of controls, P <0.01). Overexpression of thioredoxin-interacting protein (Txnip), an endogenous thioredoxin inhibitor, reduced protein synthesis in response to mechanical strain (89±5% reduction, P <0.01), phenylephrine (80±3% reduction, P <0.01), or angiotensin II (80±4% reduction, P <0.01). In vivo, myocardial thioredoxin activity increased 3.5-fold compared with sham controls after transverse aortic constriction ( P <0.01). Aortic constriction did not change thioredoxin expression but reduced Txnip expression by 40% ( P <0.05). Gene transfer studies showed that cells that overexpress Txnip develop less hypertrophy after aortic constriction than control cells in the same animals (28.1±5.2% reduction versus noninfected cells, P <0.01). Conclusions— Thus, even though thioredoxin is an antioxidant, activation of thioredoxin participates in the development of pressure-overload cardiac hypertrophy, demonstrating the dual function of thioredoxin as both an antioxidant and a signaling protein. These results also support the emerging concept that the thioredoxin inhibitor Txnip is a critical regulator of biomechanical signaling.

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“…32 Our finding that pressure overload-induced nitrotyrosine staining is markedly inhibited by EPL implicates mineralocorticoid receptors in mediating at least some of the increased oxidative stress that has been appreciated in myocardium subjected to pressure overload. 43 The mechanism by which mineralocorticoid receptors mediate oxidative stress remains to be determined. However, Sun et al 12 observed that inhibition of NADPH oxidase ameliorates the adverse myocardial effects of aldosterone, suggesting that NADPH oxidase may be a source of reactive oxygen species in response to mineralocorticoid receptors activation.…”

Section: Oxidative Stress and Inflammationmentioning

confidence: 99%

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

et al. 2005

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Background-Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. Methods and Results-We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4Ϯ0.1 versus 3.7Ϯ0.1 mm) and end-systolic (2.0Ϯ0.1 versus 2.5Ϯ0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42Ϯ2% versus 34Ϯ4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. Conclusions-Mineralocorticoid

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The antioxidant N-2-mercaptopropionyl glycine attenuates left ventricular hypertrophy in in vivo murine pressure-overload model

Abstract: Our results indicated that oxidative stress was increased in our model and that it plays an important role in the development of cardiac hypertrophy.

Cited by 142 publications

References 19 publications

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

The Antioxidant Edaravone Attenuates Pressure Overload–Induced Left Ventricular Hypertrophy

Thioredoxin-Interacting Protein Controls Cardiac Hypertrophy Through Regulation of Thioredoxin Activity

Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload

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