Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Lu, Ying; Han, Feng; Shioda, Norifumi; Moriguchi, Shigeki; Shirasaki, Yasufumi; Qin, Zheng; Fukunaga, Kohji

doi:10.1124/mol.108.050716

Cited by 20 publications

(25 citation statements)

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“…To determine whether PEP19 induced by hyper trophic stress participates in the pathological process of cardiac hypertrophy, PEP19 was transfected into rat neonatal cardiomyocytes and its effect on cardiac hypertrophy and related cell signaling were addressed in the intact cardiomyocytes. Recently we reported that a novel antagonist of calmodulin inhibits the various calmodulindependent enzymes in a competitive manner and exerts a powerful cardioprotective action during the process of cardiac hypertrophy (35,36). On the other hand, PEP19 inhibited apoptosis in PC12 cells and protected HEK293T cells against death due to Ca 2+ overload (19,20).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of PEP-19 Suppresses Angiotensin II–Induced Cardiomyocyte Hypertrophy

et al. 2014

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Abstract. The precise molecular mechanisms leading to disturbance of Ca 2+ /calmodulin dependent intracellular signalling in cardiac hypertrophy remains unclear. As an endogenous calmodulin regulator protein, the pathophysiology role of PEP19 during cardiac hypertrophy was investigated in the present study. We here demonstrated that PEP19 protein levels are significantly elevated in the aortic banding model in vivo and angiotensin II-induced cardio myocyte hypertrophy in vitro. Consistent with inhibitory actions of PEP19 on cardiomyocyte hypertrophy, induction of CaMKII and calcineurin activation as well as hypertrophyrelated genes including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was significantly inhibited by PEP19 transfection. Moreover, PEP19 partially ameliorates angiotensin II-induced elevation of phosphophospholamban (Thr17) and sarcoplasmic reticulum Ca 2+ release in cardiomyocytes. Together, our results suggest that PEP19 attenuates angiotensin II-induced cardiomyocyte hypertrophy via suppressing the disturbance of CaMKII and calcineurin signaling.

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Section: Discussionmentioning

confidence: 99%

Overexpression of PEP-19 Suppresses Angiotensin II–Induced Cardiomyocyte Hypertrophy

et al. 2014

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“…7% FBS High serum media stimulates hypertrophic growth through a different pathway by use of growth factors and glucose contained within the media (Ren et al, 2003). Our study did not seek to test the differences in GATA4 activation or CARP levels between the two hypertrophic stimuli, however several previous studies have shown that PE is a relatively stronger hypertrophic-inducing agent (Vara et al, 2003;Lu et al, 2009).…”

Section: Aim Onementioning

confidence: 99%

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

Shrout

2013

VURJ

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Cardiac hypertrophy is a growth process characterized by an increase in individual myocyte size and overall cardiac muscle mass. Although such growth can occur through physiological means such as exercise, this study examined molecular components of the pathological process that occurs in response to long-term stress, injury, or disease states. Such hypertrophic stimuli induce unique cardiac muscle growth, increasing the risk of ischemia and congestive heart failure. During the pathological process, the fundamental unit of cardiac muscle-the sarcomere-is disrupted, both as a consequence of changes in gene expression and local sarcomeric proteins. Cardiac-restricted ankyrin repeat protein (CARP) is a crucial protein that functions both in the cardiac sarcomere and at the nuclear transcriptional level. We postulated that due to this dual nature, CARP plays a key role in maintaining the cardiac sarcomere and inducing hypertrophic growth pathways. GATA4 is a transcription factor with known importance during cardiac hypertrophy. Our studies uniquely suggest that CARP and GATA4 interact, and affirm that GATA4 is activated by hypertrophic stimuli. In order to partly delineate the complex process of cardiac hypertrophy, we applied a novel approach by testing cardiomyocytes for changes in CARP levels and GATA4 activation after hypertrophic stimuli over time. Neonatal Rat Ventricular Myocytes (NRVMs) were used in this study, and induced by the stimuli agents of phenylephrine (PE) and fetal bovine serum (FBS). Aggregate results of changes in GATA4 activation over time after both stimuli did not generate a consistent trend over time and did not gain statistically significance. CARP levels over time after such stimuli, however, were documented for the first known time, and generated a relative trend of increasing then decreasing levels over time after both stimuli with relatively more significance after PE stimuli. The functional role of CARP during hypertrophic growth was clearly and significantly demonstrated in this study through immunofluorescence. Results show that hypertrophic cardiomyocyte growth was significantly blunted when NRVMs were co-treated with CARP small-interfering RNA (siRNA), which disrupts CARP function. These data suggest that CARP plays a crucial role in the hypertrophic response in cardiomyocytes, and catalyzes further study.Summer 2013 | Volume 9 |

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“…Importantly, DY-9836, an N-de-alkylated form of DY-9760e and active metabolite, promoted neuroprotective and cardioprotective effects against cardiac hypertrophy induced by endothelin-1 and angiotensin II (36,45). We also addressed an inhibitory effect of DY-9836 on uncoupling of eNOS and O 2…”

Section: Therapeutic Perspectivementioning

confidence: 99%

β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism

Han

Fukunaga

2009

J Pharmacol Sci

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Abstract. Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer's disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)-induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by β-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that β-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that peroxynitrite formation and eNOS uncoupling-mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant β-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer's disease pathology in brain.

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Phenylephrine-Induced Cardiomyocyte Injury Is Triggered by Superoxide Generation through Uncoupled Endothelial Nitric-Oxide Synthase and Ameliorated by 3-[2-[4-(3-Chloro-2-methylphenyl)-1-piperazinyl]ethyl]-5,6-dimethoxyindazole (DY-9836), a Novel Calmodulin Antagonist

Abstract: The pathophysiological relevance of endothelial nitric-oxide synthase (eNOS)-induced superoxide production in cardiomyocyte injury after prolonged phenylephrine (PE) exposure remains unclear.

Cited by 20 publications

References 50 publications

Overexpression of PEP-19 Suppresses Angiotensin II–Induced Cardiomyocyte Hypertrophy

Overexpression of PEP-19 Suppresses Angiotensin II–Induced Cardiomyocyte Hypertrophy

CARP Plays a Key Role in Cellular Growth Under Hypertrophic Stimuli in Neonatal Rat Ventricular Myocytes

β-Amyloid Accumulation in Neurovascular Units Following Brain Embolism

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