Heat shock protein 70 is secreted from endothelial cells by a non-classical pathway involving exosomes

Zhan, Rui; Leng, Xue; Liu, Xiaohua; Wang, Xinxing; Gong, Jicheng; Yan, Licheng; Wang, Liqun; Wang, Yan; Wang, Xiaoming; Lei, Qian

doi:10.1016/j.bbrc.2009.06.095

Cited by 115 publications

(76 citation statements)

References 36 publications

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“…Bilirubin is a potent antioxidant by scavenging RONS directly, and suppressing the activity of NADPH oxidase indirectly (McCarty 2007;Jansen et al 2010). Sources of circulating Hsp70 can be endothelial cells induced by oxidative lowdensity lipoprotein and homocysteine (Zhan et al 2009). Hyperhomocysteinemia triggers apoptosis in vascular endothelial cells acting as an endoplasmic reticulum stress inducer (Kyriakakis et al 2010).…”

Section: Discussionmentioning

confidence: 99%

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Serum level of soluble Hsp70 is associated with vascular calcification

Krepuska¹,

Szeberin²,

Sótonyi³

et al. 2011

Cell Stress and Chaperones

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It has been previously reported that serum levels of 70-kDa heat shock protein (Hsp70) are elevated in peripheral artery disease. The aim of the present study was to examine whether increased serum Hsp70 levels are related to the extent of arterial calcification and standard laboratory parameters of patients with peripheral artery disease, as well as to markers of inflammation (C-reactive protein), atherosclerosis (homocysteine), and calcification (fetuin-a). One hundred eighty chronic atherosclerotic patients with significant carotid stenosis and/or lower extremity vascular disease were enrolled in this crosssectional study. Systemic atherosclerosis and calcification was assessed by ultrasound (carotid intima-media thickness (IMT), presence of calcification at the abdominal aorta, carotid and femoral bifurcations, and aortic and mitral cardiac valves). Standard serum markers of inflammation, diabetes, renal function, ankle-brachial indexes, and traditional risk factors for atherosclerosis were noted. Serum Hsp70 levels were measured with enzyme-linked immunosorbent assay. Standard laboratory parameters (clinical chemistry), C-reactive protein (CRP), and homocysteine levels were determined by an autoanalyzer using the manufacturer's kits. Fetuin-a levels were measured by radial immunodiffusion. Patients' median age was 64 (57-71) years, 69% were men, and 34.5% had diabetes. Serum heat shock protein 70 levels were significantly higher in patients with more severe arterial calcification (p< 0.02) and showed significant positive correlations with serum bilirubin (r=0.23, p=0.002) and homocysteine levels (r= 0.18, p=0.02). Serum Hsp70 did not correlate with body mass index, IMT, CRP, or fetuin-a levels in this cohort. Logistic regression analysis confirmed the association between sHsp70 and calcification score (OR, 2.189; CI, p=0.016) and this correlation remained significant (OR, 2.264; CI, 1.021-5.020, p=0.044) after the adjustment for age, sex, eGFR, smoking, CRP, and homocysteine levels. Our data show that serum Hsp70 levels correlate with the severity of atherosclerosis in patients with carotid artery disease and chronic lower limb ischemia. These data support a putative role for plasma Hsp70 in the development of arterial calcification. Nevertheless, further studies are required to investigate the usefulness of circulating Hsp70 level as a marker of atherosclerotic calcification.

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Section: Discussionmentioning

confidence: 99%

“…The source of the serum Hsp70 has not been fully clarified; however, studies suggest that Hsp70 may be released from viable endothelial cells within exosomes (Zhan et al 2009). This mechanism can be induced by certain cytokines in breast adenocarcinoma (Bausero et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Serum level of soluble Hsp70 is associated with vascular calcification

Krepuska¹,

Szeberin²,

Sótonyi³

et al. 2011

Cell Stress and Chaperones

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“…The increased plasma HSP70 probably derived from multiple cells. Our previous experiments had proved that the endothelial cell could release HSP70 to plasma by an exosome-dependent pathway in the presence of Ox-LDL or Hcy (Zhan et al 2009). Ox-LDL could also induce the secretion of HSP70 from intact macrophages into the blood (Hunter-Lavin et al 2004;Svensson et al 2006).…”

Section: Discussionmentioning

confidence: 99%

“…The gray density of the band of HSP70 was measured and normalized to the gray density of the tubulin band. Plasma HSP70 release was also quantified using a Sandwich Elisa assay as previously described (Zhan et al 2009). Briefly, microtiter plates with coated HSP70/HSP72 monoclonal antibody (ADI-SPA-810, Enzo Life Sciences, Switzerland) were incubated with recombinant rat HSP70/HSP72 (ADI-SPP-758, Enzo Life Sciences, Switzerland) or plasma samples.…”

Section: Plasma Hsp70 Detection By Western Blot and Elisa Assaymentioning

confidence: 99%

Diet-induced elevation of circulating HSP70 may trigger cell adhesion and promote the development of atherosclerosis in rats

Xie¹,

Zhan²,

Yan³

et al. 2016

Cell Stress and Chaperones

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Although accumulating evidence indicates that heat shock protein 70 (HSP70) could be secreted into plasma and its levels have been found to have an ambiguous association with atherosclerosis, our knowledge for the exact role of circulating HSP70 in the development of atherosclerosis is still limited. In the present study, we report an adhesion-promoting effect of exogenous HSP70 and evaluate the potential involvement of elevated circulating HSP70 in the development of atherosclerosis. Time-dependent elevation of plasma HSP70 was found in diet-induced atherosclerotic rats, whose effect was investigated through further in vitro experiments. In rat aortic endothelial cell (RAEC) cultures, exogenous HSP70 incubation neither produced cell injuries by itself nor had protective effects on cell injuries caused by Ox-LDL or homocysteine. However, exogenous HSP70 administration could lead to a higher adhesion rate between rat peripheral blood monocytes (PBMCs) and RAECs. This adhesion-promoting effect appeared only when PBMCs, rather than RAECs, were pretreated with HSP70 incubation. PBMCs in an HSP70 environment released more IL-6 to supernatant, which subsequently up-regulated the expression of ICAM-1 in RAECs. These results indicate that the diet-induced elevation of circulating HSP70 could trigger cell adhesion with the help of IL-6 as a mediator, which provides a novel possible mechanism for understanding the role of circulating HSP70 in the pathogenesis of atherosclerosis.

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“…4,5 Additionally, endothelial cells have been demonstrated to secrete exosomes and capture exosomes from various cell types. [6][7][8][9] The transfer of signaling molecules by exosomes may thus provide a third way to regulate endothelial function. 9,10 Exosomes, small vesicles secreted by a multitude of cell types, have gained much attention for their role in intercellular communication, 11,12 immune signaling mediation, 13,14 tumor survival, 15,16 stress responses, 17,18 and angiogenesis.…”

Section: Introductionmentioning

confidence: 99%