Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy

Fang, Xi; Stroud, Matthew J.; Ouyang, Kunfu; Li, Fang; Zhang, Jianlin; Dalton, Nancy D.; Gu, Yusu; Wu, Taihu; Peterson, Kirk L.; Huang, Hsien-Da; Ju, Chen; Wang, Nanping

doi:10.1172/jci.insight.89908

Cited by 76 publications

(64 citation statements)

References 58 publications

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“…Extracellular miRNAs have recently been detected in membrane-bound vesicles from various body fluids and cell culture media (7)(8)(9). However, it has also been demonstrated by previous studies from us and others (3,(10)(11)(12)(13)) that donor cells can deliver miRNAs to recipient cells in forms independent of membrane-bound vesicles.…”

mentioning

confidence: 86%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

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

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Vascular endothelial cells (ECs) at arterial branches and curvatures experience disturbed blood flow and induce a quiescent-to-activated phenotypic transition of the adjacent smooth muscle cells (SMCs) and a subsequent smooth muscle hyperplasia. However, the mechanism underlying the flow pattern-specific initiation of EC-to-SMC signaling remains elusive. Our previous study demonstrated that endothelial microRNA-126-3p (miR-126-3p) acts as a key intercellular molecule to increase turnover of the recipient SMCs, and that its release is reduced by atheroprotective laminar shear (12 dynes/cm 2 ) to ECs. Here we provide evidence that atherogenic oscillatory shear (0.5 ± 4 dynes/cm 2 ), but not atheroprotective pulsatile shear (12 ± 4 dynes/cm 2 ), increases the endothelial secretion of nonmembrane-bound miR-126-3p and other microRNAs (miRNAs) via the activation of SNAREs, vesicleassociated membrane protein 3 (VAMP3) and synaptosomalassociated protein 23 (SNAP23). Knockdown of VAMP3 and SNAP23 reduces endothelial secretion of miR-126-3p and miR-200a-3p, as well as the proliferation, migration, and suppression of contractile markers in SMCs caused by EC-coculture. Pharmacological intervention of mammalian target of rapamycin complex 1 in ECs blocks endothelial secretion and EC-to-SMC transfer of miR-126-3p through transcriptional inhibition of VAMP3 and SNAP23. Systemic inhibition of VAMP3 and SNAP23 by rapamycin or periadventitial application of the endocytosis inhibitor dynasore ameliorates the disturbed flow-induced neointimal formation, whereas intraluminal overexpression of SNAP23 aggravates it. Our findings demonstrate the flow-pattern-specificity of SNARE activation and its contribution to the miRNA-mediated EC-SMC communication. T he interaction between hemodynamics and vascular endothelium is an important determinant of vascular homeostasis (1). In the straight part of the arteries, endothelial cells (ECs) are exposed to laminar blood flow with high shear stress that protects these parts of the vessels from atherogenesis, whereas in the branches and curvatures, the ECs experiencing disturbed flow with reciprocating and low shear stress stimulate the smooth muscle cells (SMCs) within the tunica media to become proliferative and migratory. The activated SMCs migrate into the intima, where they come into close contact with ECs and undergo phenotypic changes to lead to atherosclerosis (2). We recently demonstrated that vascular ECs repress expressions of forkhead box O3, B-cell lymphoma 2, and insulin receptor substrate 1 in the adjacent SMCs by producing microRNA-126-3p (miR-126-3p), and hence induce SMC turnover, and that the application of atheroprotective laminar shear (LS) at 12 dynes/cm 2 to ECs inhibits this paracrine effect (3). Although extracellular microRNAs (miRNAs) have been shown to convey messages from donor cells to recipient cells, how fluid shear stress regulates endothelial miRNA secretion remains to be elucidated.Emerging evidence has suggested that extracellular miRNAs can serve as not only pu...

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mentioning

confidence: 86%

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Zhu

Liu

Zhang

et al. 2017

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

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“…Cardiomyocytes from adult mouse hearts were isolated using enzymatic digestion as described previously (62) and directly lysed for Western blot analysis. Neonatal mouse cardiomyocytes (NMCMs) were prepared as previously described (63) and maintained in DMEM supplemented with 10% horse serum, 5% FBS, 100 U/ml penicillin, and 100 μg/ml streptomycin for 24 hours before treatment. GFP or mouse Bag3 cDNA (Thermo Fisher Scientific) was cloned and inserted into a 3XFlag-HA vector (gift of Rhonda Bassel-Duby, UT Southwestern Medical Center, Dallas, Texas, USA) to generate 3XFlag-HA-tagged GFP control (3XFlag-HA-GFP) and BAG3-expressing (3XFlag-HA-BAG3) vectors, respectively.…”

Section: Author Contributionsmentioning

confidence: 99%

“…Mouse HSPB8 (OriGene) fusion with photoconvertible Dendra2 fluorescent protein (64) was cloned into the pCDNA3.1 vector. 3XFlag-HA-GFP, 3XFlag-HA-BAG3, 3XFlag-HA-BEK, and Dendra2-HSPB8 adenoviruses were constructed by Welgen Inc. as previously described (63). Adenoviruses expressing Cre and lacZ (Ad-Cre and Ad-lacZ) were obtained from the UCSD Viral Vector Core.…”

Section: Author Contributionsmentioning

confidence: 99%

Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy

Fang

Bogomolovas

et al. 2017

Journal of Clinical Investigation

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119

154

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“…Collectively, the two studies above revealed a mechanism of the intra-organ cross talk, where adipose-derived exosomes transport specific protein and other molecular cargos to regulate the metabolic homeostasis positively. (Fang et al, 2016).…”

Section: Proteins and Other Cargosmentioning

confidence: 99%

Adipose‐derived exosomes: A novel adipokine in obesity‐associated diabetes

Zhang

Yang

Xiang

et al. 2019

Journal Cellular Physiology

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Dysfunction of the adipose tissue is a central driver for obesity‐associated diabetes. It is characterized by dysregulated adipokine secretion, which contributes to insulin resistance of key metabolic tissues, including the liver, skeletal muscles, and fat itself. The inter‐organ cross talk between the adipose tissue and the other organs as well as the intra‐organ cross talk between adipocytes and macrophages within the adipose tissue, traditionally mediated by hormones, was recently evidenced to be regulated by adipose‐derived exosomes. Exosomes are nano‐sized membrane‐bound vesicles secreted by the donor cells to modify intercellular communication by translating constituent nucleic acids and proteins to the target cells. Herein, we reviewed the latest progress in understanding the role of adipose‐derived exosomes in the development of insulin resistance, a key mechanism that underpins diabetes and diabetic complications, with a special focus on the role of exosomal miRNAs (micro RNAs) and proteins, and discusses the potential implications of targeting adipose tissue‐derived exosomes for diabetic therapeutics.

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Adipocyte-specific loss of PPARγ attenuates cardiac hypertrophy

Cited by 76 publications

References 58 publications

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

VAMP3 and SNAP23 mediate the disturbed flow-induced endothelial microRNA secretion and smooth muscle hyperplasia

Loss-of-function mutations in co-chaperone BAG3 destabilize small HSPs and cause cardiomyopathy

Adipose‐derived exosomes: A novel adipokine in obesity‐associated diabetes

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