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The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension.

ABSTRACT: Autoimmunity is increasingly recognized as having a central role in essential hypertension. Heat shock proteins (HSPs) are immunodominant molecules with high interspecies homology and autoimmune reactivity directed against HSP70 may play a role in the pathogenesis of hypertension. Autoimmunity to HSP70 may result from molecular mimicry between human HSP and bacterial HSP or, alternatively, as a response to HSP70-peptide complexes generated during cellular stress and delivered to the major histocompatibility complex by antigen-presenting cells. HSP70 is increased in the circulation and kidney of hypertensive patients, and genetic polymorphisms of HSP70 are associated with essential hypertension. Depending on the route and conditions of administration, HSP70 may induce or suppress immune-related inflammation. Renal inflammation induced by immunity to HSP70 causes hypertension in laboratory animals, and administration of specific peptide sequences of HSP70 results in a protective anti-inflammatory response that prevents and corrects salt-induced hypertension. Potential therapeutic uses of HSP70 in essential hypertension deserve to be investigated. LINKED ARTICLES: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc.

SUBMITTER: Rodriguez-Iturbe B

PROVIDER: S-EPMC6534783 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension.

Rodriguez-Iturbe Bernardo B Lanaspa Miguel A MA Johnson Richard J RJ

British journal of pharmacology 20180522 12

Autoimmunity is increasingly recognized as having a central role in essential hypertension. Heat shock proteins (HSPs) are immunodominant molecules with high interspecies homology and autoimmune reactivity directed against HSP70 may play a role in the pathogenesis of hypertension. Autoimmunity to HSP70 may result from molecular mimicry between human HSP and bacterial HSP or, alternatively, as a response to HSP70-peptide complexes generated during cellular stress and delivered to the major histoc ...[more]

PMID: 29679484

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Project description:Recent evidence supports a role for heat-shock protein 70 (hsp70) and the 26 S proteasome in regulating apoptosis, although the precise nature of their involvement is not known. In the present study, control and Bcl-x(L)-overexpressing, interleukin-3-dependent FL5.12 cell lines were treated with the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). Basal proteasome activity appeared to be approximately 30% lower in bcl-x(L) cells compared with control cells using a substrate for the chymotrypsin-like activity. However, no difference in proteasome activity was detected using substrates for the trypsin-like or peptidylglutamyl peptide-hydrolysing activities. In addition, protein levels of the 20 S proteasome beta-subunit, as determined by Western blot analyses, were similar in control and bcl-x(L) cells, leading to the conclusion that proteasome activities were the same in these two cell lines. At 24 h after treatment with 500 nM MG132, apoptosis in bcl-x(L) cells (22%) was less than that observed in control cells (34%). Concomitantly, caspase activity in control cells, as assessed by N-acetyl-l-aspartyl-l-glutamyl-l-valyl-l-aspartyl-7-amino-4-methylcou marin (Ac-DEVD-AMC), was twice that observed in bcl-x(L) cells. By 48 h after MG132 treatment, apoptosis and caspase activity in bcl-x(L) cells were similar to those observed in control cells at 24 h. Proteasome inhibition stimulated increases in hsp70 protein levels in control and bcl-x(L) cells by 12 h, although the maximal increases found in bcl-x(L) cells were less. Blocking this induction with hsp70 antisense oligonucleotides potentiated apoptosis after treatment with MG132. Inhibiting caspase activity with a broad-spectrum caspase inhibitor, t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone, prevented MG132-induced apoptosis. The more specific caspase-3 inhibitor, Ac-DEVD-aldehyde, afforded less protection, although both inhibitors completely inhibited Ac-DEVD-AMC cleavage. These data indicate that both hsp70 and Bcl-x(L) provide some protection against proteasome inhibitor-induced apoptosis.

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The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension.

Publications

The role of autoimmune reactivity induced by heat shock protein 70 in the pathogenesis of essential hypertension.

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