Down-regulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II–angiotensin type 1 receptor system

Iwanaga, Yoshitaka; Kihara, Yasuki; Takenaka, Hiroyuki; Kita, Toru

doi:10.1016/j.yjmcc.2006.07.004

Cited by 139 publications

(113 citation statements)

References 27 publications

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“…5,8 Recent studies have revealed that APJ and AT 1 have similar expression patterns in a number of physiological and pathophysiological states, and apelin-APJ contributes to opposing effects against Ang II-AT 1 . 10,11 Blood pressure in AT 1 and APJ double-knockout mice was significantly elevated compared with that in AT 1 knockout mice. 11 Chun et al reported that apelin-APJ antagonizes Ang II-AT 1 by increasing nitric oxide (NO) production via intracellular signaling in mouse models of atherosclerosis.…”

Section: Introductionmentioning

confidence: 89%

“…3,4 Since its discovery, the apelin-APJ system has emerged as an important regulator of cardiovascular homeostasis and may have a critical role in the pathophysiological development of cardiovascular diseases; it has also been regarded as a new therapeutic research and drug design target. [5][6][7][8][9][10][11] The functions of apelin-APJ appear to be complex and have yet to be defined by consensus. The accumulating evidences have indicated that the functions of apelin-APJ may be dependent on its target organs and its physiological/pathophysiological state.…”

Section: Introductionmentioning

confidence: 99%

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Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

et al. 2011

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Apelin and its G-protein-coupled receptor APJ are potent regulators of the cardiovascular system. Recent studies have suggested that apelin-APJ reverses the function of angiotensin II (Ang II)-the Ang II type 1 receptor (AT 1 ). However, the mechanism remains unclear because of the accumulating evidences that apelin-APJ may contribute to both cardioprotection and pathological progression. In human embryonic kidney 293 cells, we found that coexpression with APJ significantly suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by Ang II-AT 1 , whereas apelin abolished this attenuation through activated APJ independently of its heterodimerization. Pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the ERK1/2 phosphorylation level similar to that found with AT 1 and APJ coexpression without apelin stimulation. In contrast, coexpression of the beta-2-adrenergic receptor or the pharmacologically non-activated Ang II type 2 receptor (AT 2 ) pretreated with the AT 2 -specific antagonist, PD123319, did not affect ERK1/2 phosphorylation through AT 1 . Pretreatment with 30 nM of the AT 1 blocker (ARB) TA-606A suppressed 50% of the AT 1 -mediated ERK1/2 phosphorylation, whereas 30 nM of TA-606A achieved 75% suppression when the non-activated APJ was coexpressed without ligand or PTX. However, 120 nM of TA-606A failed to reach the target phosphorylation when it was coexpressed with activated APJ with apelin. Based on these results, we demonstrated that non-activated APJ may suppress Ang II-AT 1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may be relevant to the potential contribution of apelin-APJ to ARB treatment in the clinical realm.

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Section: Introductionmentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

et al. 2011

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“…Animal models of heart failure demonstrate cardiac apelin to be downregulated by angiotensin II. This cardiac apelin is restored by treatment with angiotensin type 1 blocker (Iwanaga et al 2006). However, myocardial expression of apelin is increased in ischaemic heart failure (Atluri et al 2007).…”

Section: Apelinmentioning

confidence: 98%

Role of adipokines in cardiovascular disease

Mattu¹,

Randeva²

2012

Journal of Endocrinology

245

203

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The discovery of leptin in 1994 sparked dramatic new interest in the study of white adipose tissue. It is now recognised to be a metabolically active endocrine organ, producing important chemical messengers -adipokines and cytokines (adipocytokines). The search for new adipocytokines or adipokines gained added fervour with the prospect of the reconciliation between cardiovascular diseases (CVDs), obesity and metabolic syndrome. The role these new chemical messengers play in inflammation, satiety, metabolism and cardiac function has paved the way for new research and theories examining the effects they have on (in this case) CVD. Adipokines are involved in a 'good-bad', yin-yang homoeostatic balance whereby there are substantial benefits: cardioprotection, promoting endothelial function, angiogenesis and reducing hypertension, atherosclerosis and inflammation. The flip side may show contrasting, detrimental effects in aggravating these cardiac parameters.

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“…Ishida et al have reported differences in blood pressure response in mice lacking both the Ang II receptor type I (AT1R) and APJ compared with mice lacking only AT1R (13). In a hypertensive model of heart failure, Iwanaga et al showed that Ang II inhibits expression of apelin and APJ, perhaps contributing to cardiac decompensation (19).…”

Section: Introductionmentioning

confidence: 99%

Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis

Chun¹,

Ali²,

Kojima³

et al. 2008

J. Clin. Invest.

221

269

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Apelin and its cognate G protein-coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II-mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II-mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.

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Down-regulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II–angiotensin type 1 receptor system

Cited by 139 publications

References 27 publications

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

Role of adipokines in cardiovascular disease

Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis

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