Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice

You, J. Q.; Wu, Jian; Jia, Guanghong; Guo, Jing; Wang, Shijun; Li, Lei; Ge, Junbo; Zou, Yunzeng

doi:10.1097/fjc.0b013e31827a0278

Cited by 33 publications

(40 citation statements)

References 41 publications

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“…In a sense, our results may be considered as an extension of previous findings that an angiotensin receptor blocker can decrease CaMKIIδ expression and reverse cardiac hypertrophy in stroke-prone, spontaneously hypertensive rats [34]. Together with other findings that an angiotensin receptor blocker attenuates cardiac remodeling in pressure-overload mice through DLL4/Notch1 pathway activation [18] and suppresses β-adrenergic receptor stimulation-induced cardiac hypertrophy via the Raf/MEK/ERK cascade [15], we further suggest that angiotensin receptor blockers inhibit multiple intracellular signaling pathways to elicit their prevention of cardiac remodeling. From this point of view, this study offers insight into the therapeutic efficacy of valsartan in treating cardiac hypertrophy.…”

Section: Discussionsupporting

confidence: 82%

“…In different models of cardiac hypertrophy, angiotensin II, via AT1, activates several intracellular signaling pathways, e.g. mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK1/2) signaling [16], Akt/glycogen synthase kinase (GSK)-3β/mammalian target of rapamycin (mTOR) pathway [17], Raf/MEK/ERK cascade [15] and delta-like ligand 4 (DLL4)/Notch1 pathway [18] in aortic banding-, thyroid hormone-, isoproterenol- and transverse aortic constriction-induced cardiac hypertrophy, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Valsartan, as an angiotensin receptor blocker, can be used to prevent or reverse cardiac hypertrophy, caused by multiple factors, via multiple signaling pathways [13,14,15,16,17,18]. In this study, we aimed to investigate whether the signaling pathway of Dyrk1A-ASF-CaMKIIδ was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats.…”

Section: Introductionmentioning

confidence: 99%

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Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Yao

Qin²,

Zhu³

et al. 2015

Cardiology

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Objectives: It is known that the expression, activity and alternative splicing of Ca²⁺/calmodulin-dependent protein kinase IIδ (CaMKIIδ) are dysregulated in the cardiac remodeling process. Recently, we found a further signaling pathway, by which dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) regulates the alternative splicing of CaMKIIδ via the alternative splicing factor (ASF), i.e. Dyrk1A-ASF-CaMKIIδ. In this study, we aimed to investigate whether Dyrk1A-ASF-CaMKIIδ signaling was involved in valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats. Methods: Rats were subjected to two kidney-one clip (2K1C) surgery and then treated with valsartan (30 mg/kg/day) for 8 weeks. Hypertrophic parameter analysis was then performed. Western blot analysis was used to determine the protein expression of Dyrk1A and ASF and RT-PCR was used to analyze the alternative splicing of CaMKIIδ in the left ventricular (LV) sample. Results: Valsartan attenuated cardiac hypertrophy in 2K1C rats but without impairment of cardiac systolic function. Increased protein expression of Dyrk1A and decreased protein expression of ASF were observed in the LV sample of 2K1C rats. Treatment of 2K1C rats with valsartan reversed the changes in Dyrk1A and ASF expression in the LV sample. Valsartan adjusted the 2K1C-induced imbalance in alternative splicing of CaMKIIδ by upregulating the mRNA expression of CaMKIIδC and downregulating the mRNA expression of CaMKIIδA and CaMKIIδB. Conclusions: Valsartan inhibition of cardiac hypertrophy in renovascular hypertensive rats was mediated, at least partly, by Dyrk1A-ASF-CaMKIIδ signaling.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Yao

Qin²,

Zhu³

et al. 2015

Cardiology

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“…Echocardiographic analyses were performed before (baseline) and at 2 and 4 weeks post TAC in mice, as we described previously 14, 19. Briefly, Transthoracic echocardiography was performed with an animal specific instrument (Vevo770; VisualSonics, Toronto, ON, Canada).…”

Section: Methodsmentioning

confidence: 99%

“…Aortic blood pressure (ABP) and LV pressure (LVP) were evaluated at 2 and 4 weeks after surgery, as we described previously 14, 19. Briefly, after anaesthesia, a micromanometer (Millar 1.4F, SPR 835; Millar Instruments, Houston, TX, USA) was inserted through the right common carotid artery into the aorta and carefully introduced into LV.…”

Section: Methodsmentioning

confidence: 99%

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

Zhang

Liu

Jiang

et al. 2015

J Cellular Molecular Medi

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Inflammation plays a key role in pressure overload‐induced cardiac hypertrophy and heart failure, but the mechanisms have not been fully elucidated. High‐mobility group box 1 (HMGB1), which is increased in myocardium under pressure overload, may be involved in pressure overload‐induced cardiac injury. The objectives of this study are to determine the role of HMGB1 in cardiac hypertrophy and cardiac dysfunction under pressure overload. Pressure overload was imposed on the heart of male wild‐type mice by transverse aortic constriction (TAC), while recombinant HMGB1, HMGB1 box A (a competitive antagonist of HMGB1) or PBS was injected into the LV wall. Moreover, cardiac myocytes were cultured and given sustained mechanical stress. Transthoracic echocardiography was performed after the operation and sections for histological analyses were generated from paraffin‐embedded hearts. Relevant proteins and genes were detected. Cardiac HMGB1 expression was increased after TAC, which was accompanied by its translocation from nucleus to both cytoplasm and intercellular space. Exogenous HMGB1 aggravated TAC‐induced cardiac hypertrophy and cardiac dysfunction, as demonstrated by echocardiographic analyses, histological analyses and foetal cardiac genes detection. Nevertheless, the aforementioned pathological change induced by TAC could partially be reversed by HMGB1 inhibition. Consistent with the in vivo observations, mechanical stress evoked the release and synthesis of HMGB1 in cultured cardiac myocytes. This study indicates that the activated and up‐regulated HMGB1 in myocardium, which might partially be derived from cardiac myocytes under pressure overload, may be of crucial importance in pressure overload‐induced cardiac hypertrophy and cardiac dysfunction.

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Ginkgolide A targets forkhead box O1 to protect against lipopolysaccharide‐induced septic cardiomyopathy

Wang

Zhao

et al. 2023

Phytotherapy Research

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Ginkgolide A (GA), a main terpenoid extracted from Ginkgo biloba, possesses biological activities such as anti-inflammatory, anti-tumor, and liver protection. However, the inhibitory effects of GA on septic cardiomyopathy remain unclear. This study aimed to explore the effects and mechanisms of GA in countering sepsis-induced cardiac dysfunction and injury. In lipopolysaccharide (LPS)-induced mouse model, GA alleviated mitochondrial injury and cardiac dysfunction. GA also significantly reduced the production of inflammatory and apoptotic cells, the release of inflammatory indicators, and the expression of oxidative stress-associated and apoptosis-associated markers, but increased the expression of pivotal antioxidant enzymes in hearts from LPS group. These results were consistent with those of in vitro experiments based on H9C2 cells. Database analysis and molecular docking suggested that FoxO1 was targeted by GA, as shown by stable hydrogen bonds formed between GA with SER-39 and ASN-29 of FoxO1. GA reversed LPS-induced downregulation of nucleus FoxO1 and upregulation of p-FoxO1 in H9C2 cells. FoxO1 knockdown abolished the protective properties of GA in vitro. KLF15, TXN2, NOTCH1, and XBP1, as the downstream genes of FoxO1, also exerted protective effects. We concluded that GA could alleviate LPS-induced septic cardiomyopathy via binding to FoxO1 to attenuate cardiomyocyte inflammation, oxidative stress, and apoptosis.

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Olmesartan Attenuates Cardiac Remodeling Through DLL4/Notch1 Pathway Activation in Pressure Overload Mice

Abstract: Our findings identify a heretofore unknown pharmacological mechanism that olmesartan improves cardiac remodeling and function via DLL4/Notch1 pathway activation in mice with chronic pressure overload, which may present a new therapeutic target for hypertension.

Cited by 33 publications

References 41 publications

Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Dyrk1A-ASF-CaMKIIδ Signaling Is Involved in Valsartan Inhibition of Cardiac Hypertrophy in Renovascular Hypertensive Rats

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

Ginkgolide A targets forkhead box O1 to protect against lipopolysaccharide‐induced septic cardiomyopathy

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