Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1

Hayashi, Doubun; Kudoh, Sumiyo; Shiojima, Ichiro; Zou, Yunzeng; Harada, Koichiro; Shimoyama, Masaki; Imai, Yasushi; Monzen, Koshiro; Yamazaki, Tsutomu; Yazaki, Yoshio; Nagai, Ryozo; Komuro, Issei

doi:10.1016/j.bbrc.2004.07.119

Cited by 66 publications

(52 citation statements)

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“…The antihypertrophic and growth inhibitory effects of ANP have been well described in vitro and in vivo and involve increases in intracellular cGMP concentrations (5,22,29). The decreases in HW͞BW ratios reported in this article are similar in many ways to the cardiac changes reported with administration of the PDE5A inhibitor sildenafil, which blocks the breakdown of intracellular cGMP (30).…”

Section: Discussionsupporting

confidence: 68%

“…Atrial natriuretic peptide (ANP), a 27-aa peptide hormone with potent vasodilatory, natriuretic, diuretic, and antihypertrophic effects, is an attractive candidate gene product for antihypertensive therapy (4,5). Studies involving the infusion of synthetic ANP to humans with HTN have demonstrated significant decreases in blood pressure and brisk natriuresis͞diuresis associated with peptide administration (6,7).…”

mentioning

confidence: 99%

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Regulatable atrial natriuretic peptide gene therapy for hypertension

Schillinger

Tsai

Taffet

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Hypertension (HTN) is a disease that begins with dysfunctional renal-sodium excretion and progresses to a syndrome of highly elevated systolic, diastolic, and mean arterial pressures. Inadequacies in the therapy of HTN have led to the investigation of the gene therapy of this disease by using systemic overproduction of vasodilatory peptides, such as atrial natriuretic peptide (ANP). However, gene-therapy approaches to HTN using ANP are limited by the need for long-term ANP gene expression and, most important, control of ANP gene expression. Here, we introduce a helperdependent adenoviral vector carrying the mifepristone (Mfp)-inducible gene-regulatory system to control in vivo ANP expression. In the BPH͞2 mouse model of HTN, Mfp-inducible ANP expression was seen for a period of >120 days after administration of vector. Physiological effects of ANP, including decreased systolic blood pressure, increased urinary cGMP output, and decreases in heart weight as a percentage of body weight were also under the control of Mfp. Given these capabilities, this vector represents a paradigm for the gene therapy of HTN. adenovirus ͉ mifepristone-inducible H ypertension (HTN) is a disease that is characterized by chronically elevated arterial blood pressure that affects Ϸ25-35% of the population in developed countries, and it is one of the leading causes of morbidity and mortality in adults (1). Development of HTN is likely to involve defects in renal-sodium handling that are exacerbated by maladaptive activation of neurohormonal compensatory mechanisms. The morbidity and mortality caused by the hypertensive state are a consequence of detrimental effects that manifest predominantly in the heart, brain, and kidney and are referred to collectively as hypertensive end-organ disease. Typically, endorgan disease involves pathological left-ventricular hypertrophy, a propensity toward cerebrovascular accidents, and accelerated renal atherosclerosis (1, 2).The current therapy of HTN has been rationally designed to address the recognized causes of hypertensive pathophysiology, including impaired urinary-sodium excretion and neurohormonal compensatory-mechanism activation. Also, in recognition of the fact that hypertensive end-organ disease represents the true danger of chronically elevated arterial blood pressure, the main goals of antihypertensive therapy have evolved to include a reduction in blood pressure as well as prevention of cardiovascular, cerebrovascular, and renal pathology associated with elevated blood pressure (2, 3). However, a multitude of studies have revealed that no available drug therapy for HTN has the capability to cure the hypertensive state or reverse or prevent the pathological changes associated with hypertensive end-organ disease fully (2). As a result, therapeutic approaches to HTN involving gene therapy have been of recent interest.Atrial natriuretic peptide (ANP), a 27-aa peptide hormone with potent vasodilatory, natriuretic, diuretic, and antihypertrophic effects, is an attractive candidate gene product f...

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Section: Discussionsupporting

confidence: 68%

mentioning

confidence: 99%

Regulatable atrial natriuretic peptide gene therapy for hypertension

Schillinger

Tsai

Taffet

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…A similar mechanism of action has been described for ANP type-A in cardiomyocytes. 87 Cycloheximide increased levels of p21 in response to neurotrophins, and increased levels of cyclin D1 in response to CNP combined with neurotrophins. These data suggest that protein synthesis is utilized to reduce levels of antagonistic cell cycle regulatory proteins through increased protein degradation.…”

Section: © 2 0 0 7 L a N D E S B I O S C I E N C E D O N O T D I S mentioning

confidence: 96%

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Simpson

Moon²,

Kleman

et al. 2007

Cell Cycle

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ACKnowlEdGEMEntSWe thank Amy Palmer for helpful discussions and reading of the manuscript, and Susan McTeer for manuscript preparation. This work was supported by grants NIDCD RO3 DC005704 to P.J.S., NIDCD RO1 DC02979 and NINDS RO1 NS39657 to G.V.R. AbStRACtNeuronal stem cell expansion and differentiation is a process involving stages of proliferation and maturation governed by the sequential and combinatorial exposure of cells to extrinsic factors. The olfactory epithelium is an excellent model to investigate regulation of this process, as it undergoes neuronal replacement post-natally. We have shown that the neurotrophins NGF and BDNF sequentially promote proliferation of developing olfactory sensory neuronal precursors, although their kinetics of proliferation and cell fate outcomes differ. Interestingly, CNP inhibits this neurotrophin-induced proliferation and promotes the maturation of these precursors to their next developmental stage. Here, we investigate the mechanisms behind these actions. Both NGF and BDNF increase the expression of cyclin D1 and cyclin-dependent kinase 4 (cdk4), with temporal expression patterns that parallel the proliferation kinetics of their cellular targets. The timing of cyclin D1 expression reflects differences in the need for transcription and translation in early and late stage precursors. CNP inhibits neurotrophin-induced cyclin D1 expression, and induces the expression of different profiles of inhibitory cell cycle proteins, which are neurotrophin-specific and correlate with the attainment of different maturational cell fates. Inhibition of protein degradation reverses the effects of neurotrophins and CNP on cyclin D1 and inhibitor expression levels, respectively. These results suggest a model for cell cycle regulation that involves the simultaneous expression of progressive and inhibitory cell cycle regulatory proteins in response to both proliferation and differentiation agents, followed by selective degradation of these proteins, providing a mechanism for rapid and exquisite control of the cell cycle.

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“…Studies on cultured cardiomyocytes have shown that ANP opposes agonist-induced hypertrophy through cGMP formation and enhanced expression of MAPK phosphatase-1. 19 In addition, activation of cGMP-dependent protein kinase type I (PKG I) by NO and cGMP was shown to inhibit the hypertrophic calcineurin-NFAT signaling pathway in cultured cardiomyocytes in part by inhibiting L-type Ca 2ϩ channels. 20 Intriguingly, long-acting dihydropyridine Ca 2ϩ channel blockers were shown to inhibit cardiac hypertrophy induced by chronic NOS inhibition in the rat, 21 although the involvement of L-type Ca 2ϩ channels in cardiac hypertrophy is not established.…”

Section: Atrial Natriuretic Peptide Signalingmentioning

confidence: 99%

Putting the Brakes on Cardiac Hypertrophy

Booz

2005

Hypertension

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Abstract-We know a great deal about the receptors and signaling pathways in cardiomyocytes that contribute to hypertrophic growth. Although drugs that target them have proven effective in substantially reducing left ventricular hypertrophy and associated mortality, cardiovascular disease remains the leading cause of death in the West. Another approach may rest with exploiting naturally occurring regulators of maladaptive cardiac hypertrophy that have been identified in the past few years. These endogenous negative regulators can be grouped, for the most part, into those constitutively active but whose activity is decreased by hypertrophic stimulation, and those with little or no baseline activity that are activated by hypertrophic stimulation. Spanning both groups are 4 systems that converge on cyclic guanosine 3Ј, 5Ј-monophosphate (cGMP) generation, namely natriuretic peptides (ANP and BNP), kinins, nitric oxide (NO), and the angiotensin II type 2 receptor (AT 2 ). Although holding promise as a means for restricting hypertrophy, each of these signaling molecules has certain limitations that need to be overcome. What follows is an overview of research over the past 2 years, much of it published in Hypertension, which has dealt with the antihypertrophic action of this particular group of endogenous signaling molecules. Understanding the function and regulation of the antihypertrophic NO-cGMP system offers the promise of novel therapeutic strategies for treating cardiac hypertrophy and heart failure. Key Words: adrenergic antagonists Ⅲ angiotensin II Ⅲ kinins Ⅲ natriuretic peptides Ⅲ nitric oxide synthase Ⅲ statins V arious disease states that impose an additional workload on the heart, including hypertension and myocardial infarction, lead to left ventricular (LV) hypertrophy. 1 The increase in LV mass is largely caused by increased size and protein content of cardiomyocytes and was once viewed as an adaptive response for maintaining cardiac output and tissue perfusion. After more than a decade of study, however, LV hypertrophy is recognized as a maladaptive response associated with untoward events, such as cardiomyocyte fetal gene re-expression, apoptosis, and interstitial fibrosis. 1 Untreated, LV hypertrophy generally progresses to ventricular dilatation, systolic and diastolic contractile dysfunction, and heart failure. In fact, LV hypertrophy represents a well-established risk factor for cardiovascular mortality. 2 Even the premise that cardiac hypertrophy is required to preserve heart function and normalize wall stress under conditions of pressure overload is challenged by recent studies. 1,3,4 Drugs targeting receptors and signaling pathways that couple to cardiomyocyte hypertrophic growth are highly effective in reducing LV hypertrophy and associated mortality. Yet cardiovascular disease remains the leading cause of death in the West. 5 Is there another strategy that could be used to control or reverse LV hypertrophy? An answer may rest with naturally occurring regulators of cardiac hypertrophy identified...

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Atrial natriuretic peptide inhibits cardiomyocyte hypertrophy through mitogen-activated protein kinase phosphatase-1

Cited by 66 publications

References 31 publications

Regulatable atrial natriuretic peptide gene therapy for hypertension

Regulatable atrial natriuretic peptide gene therapy for hypertension

Progressive and Inhibitory Cell Cycle Proteins Act Simultaneously to Regulate Neurotrophin-mediated Proliferation and Maturation of Neuronal Precursors

Putting the Brakes on Cardiac Hypertrophy

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