Cardiac myocyte p38α kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart

Rose, Beth; Yokota, Tomohiro; Chintalgattu, Vishnu; Ren, Shuxun; Iruela‐Arispe, M. Luisa; Khakoo, Aarif Y.; Minamisawa, Susumu; Wang, Yibin

doi:10.1074/jbc.m117.784553

Cited by 28 publications

(20 citation statements)

References 44 publications

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“…Canonically, growth factors such as VEGF activate a broad range of pathways including Akt (protein kinase B), endothelial nitric oxide synthase (eNOS), and p38 MAPK to promote EC functions that are necessary for successful angiogenesis. In particular, p38 phosphorylation and signaling have been shown to promote angiogenesis in response to myocardial damage, cardiac remodeling, and peripheral tissue ischemia (16, 17). Collectively, these data suggest that correction of pathways downstream of growth factor activation can rescue proangiogenic responses and improve therapeutic angiogenesis.…”

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confidence: 99%

MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells

Icli

Ozdemir

et al. 2019

FASEB j.

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Angiogenesis is a critical process in repair of tissue injury that is regulated by a delicate balance between pro‐ and antiangiogenic factors. In disease states associated with impaired angiogenesis, we identified that miR‐135a‐3p is rapidly induced and serves as an antiangiogenic microRNA (miRNA) by targeting endothelial cell (EC) p38 signaling in vitro and in vivo. MiR‐135a‐3p overexpression significantly inhibited EC proliferation, migration, and network tube formation in matrigel, whereas miR‐135‐3p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3′‐UTR reporter and miRNA ribonucleoprotein complex ‐immunoprecipitation assays, and small interfering RNA dependency studies revealed that miR‐135a‐3p inhibits the p38 signaling pathway in ECs by targeting huntingtin‐interacting protein 1 (HIP1). Local delivery of miR‐135a‐3p inhibitors to wounds of diabetic db/db mice markedly increased angiogenesis, granulation tissue thickness, and wound closure rates, whereas local delivery of miR‐135a‐3p mimics impaired these effects. Finally, through gain‐ and loss‐of‐function studies in human skin organoids as a model of tissue injury, we demonstrated that miR‐135a‐3p potently modulated p38 signaling and angiogenesis in response to VEGF stimulation by targeting HIP1. These findings establish miR‐135a‐3p as a pivotal regulator of pathophysiological angiogenesis and tissue repair by targeting a VEGF‐HIP1‐p38K signaling axis, providing new targets for angiogenic therapy to promote tissue repair.—Icli, B., Wu, W., Ozdemir, D., Li, H., Haemmig, S., Liu, X., Giatsidis, G., Cheng, H. S., Avci, S. N., Kurt, M., Lee, N., Guimaraes, R. B., Manica, A., Marchini, J. F., Rynning, S. E., Risnes, I., Hollan, I., Croce, K., Orgill, D. P., Feinberg, M. W. MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells. FASEB J. 33, 5599–5614 (2019). http://www.fasebj.org

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confidence: 99%

MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells

Icli

Ozdemir

et al. 2019

FASEB j.

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“…However, IL4 is an anti-in ammatory cytokine that inhibits the expression and release of in ammatory cytokines such as IL-1, IL-6, and TNF-α [43][44]. Szkodzinski et al [45] have determined prognostic implications of IL-4 in developing severe cardiac dysfunction in the course of acute myocardial infarction (AMI). In addition, AKT1 is the main isomer in vascular endothelial cells, which plays a crucial role in cardiac growth, contraction and coronary angiogenesis [46].…”

Section: Discussionmentioning

confidence: 99%

A Network Pharmacology Analysis to Reveal the Molecular Mechanism of Zhizi-Danshen on Coronary Heart Disease

Shen¹,

Wang²,

Wu³

et al. 2020

Preprint

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ObjectiveOur study aimed to investigate the potential mechanisms of the herb pair Zhizi-Danshen (ZD) for coronary heart disease (CHD) using network pharmacological data mining technology.MethodsThe Traditional Chinese Medicine System Pharmacology (TCMSP) database was used to collect the active ingredients of ZD and predict ZD-related target proteins. Afterwards, we identified CHD-related targets from DisGeNET database, NCBI gene database, and TTD database. The common targets both from ZD and CHD were screened by Venny2.1, which were then imported into the String database for protein-protein interaction (PPI) analysis. Finally, the GO and KEGG enrichment analysis were performed by R software, and the network construction was established using Cytoscape3.7.2.ResultsWe obtained 199 possible targets from 62 candidate ingredients of ZD and 1033 CHD-ralated targets, with 83 overlapping common target genes. Then, 11 core targets were acquired from PPI network analysis. Further, GO analysis showed that these common targets mainly influenced receptor ligand activity，cytokine activity，cytokine receptor binding，steroid hormone receptor activity, and peptide binding. KEGG pathway analysis indicated that ZD affected CHD through seven important pathways linked to vascular endothelial function regulation (fluid shear stress and atherosclerosis，AGE-RAGE signaling pathway in diabetic complications, HIF-1 signaling pathway), imflammatory effects (IL-17 signaling pathway, TNF signaling pathway，Toll-like receptor signaling pathway)，and hormone regulation (relaxin signaling pathway). ConclusionsThis study revealed the potential pharmacological mechanisms of ZD against CHD, which were mainly associated with regulation of vascular endothelial function and inflammatory effects, promotion of vasodilatation, and prevention of cardiac fibrosis. Moreover, it provided a novel conception for the development of alternative therapies on CHD.

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“…Since endothelial cell activation proceeding to endothelial dysfunction was commonly observed, endothelial activation / dysfunction has been studied as two converging concepts. The influence and regulation of endothelial activation / dysfunction has been strongly correlated with the pathogenesis of complex disease processes such as diabetes (Jia et al, 2017, Watt et al, 2017, maladaptive cardiac remodelling (Rose et al, 2017, Tsai et al, 2017, and atherosclerosis (Corban et al, 2017).…”

Section: Endothelial Cell Activation and Dysfunctionmentioning

confidence: 99%

“…There is evidence that cardiac angiogenesis is enhanced during the acute phase of adaptive cardiac growth (e.g., in endurance athletes) but reduced as hearts undergo pathological remodelling. Enhanced angiogenesis in adaptive remodelling was associated with myocardial VEGF and angiopoietin-2 release, whereas inhibition of VEGF in maladaptive remodelling led to decreased capillary density and impaired cardiac function (Shiojima et al, 2005, Rose et al, 2017. NO production also plays a critical role in the mechanism that couples cardiac angiogenesis to cardiomyocyte growth.…”

Section: Angiogenesis and Cardiac Hypertrophymentioning

confidence: 99%

Endothelial cell modulation of cardiomyocyte gene expression

Jiang

Mohr

Ullrich

et al. 2019

Experimental Cell Research

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WB Western blot WGA Wheat germ agglutinin β-MHC -Myosin heavy chain 2013, Fredriksen et al., 2001). Kidney disease is commonly found in heart failure (HF) patients (Grande et al., 2017). It was found that GFR is associated with the degree of cardiac diastolic dysfunction and adverse clinical outcomes (Jain et al., 2017). A recent nationwide population-based cohort study showed that heart failure patients have a higher risk of developing dementia (Adelborg et al., 2017). Studies also revealed post-mortem that 73.6% ± 7.0% of all cardiomyocytes were mono-nucleated, 25.5% ± 7.4% were bi-nucleated, and 1.0% ± 1.2% were tri-nucleated in the heart of individuals aged one month to 73 years. In agreement with previous studies (Mollova et al., 2013, Olivetti et al., 1996), they established that already 1 month after birth; the final number of cardiomyocytes was reached (3.2 ± 0.75 × 10 9 cells) and remained constant throughout life. By stereological measuring the average volume of cardiomyocytes at different ages, it was found that the adaptive about 3-fold greater (endothelium-derived contracting factors) (Flammer et al., 2012). Furchgott and Zawadzki (Furchgott and Zawadzki, 1980) first described the phenomenon of endothelium-dependent relaxation in 1980. Subsequently, the identification of nitric oxide (NO) as the crucial endothelium-derived mediator of vascular relaxation led to substantial progress in cardiovascular research (Flammer et al., 2012). In addition to with arterial hypertension and echocardiographically documented left ventricular hypertrophy, who received either the AT 1 receptor blocker losartan or the β 1 receptor blocker atenolol, were much less likely to experience such a major cardiovascular event (Kjeldsen et al., 2002). Also whereby NT-proBNP levels are more sensitive and specific to distinguish HF from non-HF subjects (Fonseca et al., 2004). NT-proBNP levels were also suggested to be highly predictive of incident atrial fibrillation, the most common cardiac rhythm abnormality, after adjustment for an extensive number of covariates (Patton et al., 2009). Although ANP and BNP have been recommended to provide prognostic information

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Cardiac myocyte p38α kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart

Cited by 28 publications

References 44 publications

MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells

MicroRNA‐135a‐3p regulates angiogenesis and tissue repair by targeting p38 signaling in endothelial cells

A Network Pharmacology Analysis to Reveal the Molecular Mechanism of Zhizi-Danshen on Coronary Heart Disease

Endothelial cell modulation of cardiomyocyte gene expression

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