Chloroquine improves the response to ischemic muscle injury and increases HMGB1 after arterial ligation

Jun Xu; Xiangdong Cui; Jiehua Li; Panagiotis Koutakis; Iraklis Pipinos; Edith Tzeng; Alex Chen; Ulka Sachdev

doi:10.1016/j.jvs.2017.01.021

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Chloroquine improves the response to ischemic muscle injury and increases HMGB1 after arterial ligation

Journal article

Open access

Peer reviewed

Chloroquine improves the response to ischemic muscle injury and increases HMGB1 after arterial ligation

Jun Xu, Xiangdong Cui, Jiehua Li, Panagiotis Koutakis, Iraklis Pipinos, Edith Tzeng, Alex Chen and Ulka Sachdev

Journal of vascular surgery, Vol.67(3), pp.910-921

03/2018

DOI: 10.1016/j.jvs.2017.01.021

PMCID: PMC5581296

PMID: 28259568

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Abstract

We have previously shown that exogenous administration of the nuclear protein high mobility group box 1 (HMGB1) improves angiogenesis after tissue ischemia. Antagonizing HMGB1 prolongs muscle necrosis and deters regeneration. In this study, we evaluated HMGB1 expression in peripheral arterial disease (PAD) and the mechanisms that promote its release in a murine model of hindlimb ischemia. Specifically, we investigated how chloroquine (CQ), a commonly employed disease-modifying antirheumatic drug, promotes HMGB1 release from muscle. We hypothesized that CQ could increase HMGB1 locally and systemically, allowing it to mediate recovery from ischemic injury. Muscle biopsies were performed on patients undergoing lower extremity surgery for non-PAD-related disease as well as for claudication and critical limb ischemia. Clinical symptoms and ankle-brachial indices were recorded for each patient. HMGB1 was detected in muscle sections using immunohistochemical staining. Unilateral femoral artery ligation was performed on both wild-type and inducible HMGB1 knockout mice. Wild-type mice were administered intraperitoneal CQ 2 weeks before and after femoral artery ligation. Laser Doppler perfusion imaging was used to determine perfusion recovery. Serum and tissue levels of HMGB1 were measured at designated time points. In vitro, cultured C2C12 myoblasts were treated with increasing doses of CQ. HMGB1, autophagosome formation, p62/SQSTM1 accumulation, caspase-1 expression and activity, and lactate dehydrogenase levels were measured in supernatants and cell lysates. Nuclear expression of HMGB1 was prominent in patients with claudication and critical limb ischemia (P < .05) compared with controls. CQ-treated mice had elevated serum HMGB1 and diffuse HMGB1 staining in muscle (P < .01). In wild-type mice, CQ treatment resulted in higher laser Doppler perfusion imaging ratios in the ischemic limb at 7 days (P < .03) and less fat replacement after 2 weeks (P < .03). In cultured myoblasts, CQ induced autophagosome accumulation, inhibited p62/SQSTM-1 degradation, and activated caspase-1. HMGB1 is prominently expressed in PAD muscle but mostly confined to the nucleus. Our in vivo data suggest that HMGB1 mobilization into the sarcoplasm and serum can be increased with CQ, possibly through caspase-1-mediated pathways. Whereas HMGB1 can be released by many cell types, these studies suggest that the muscle may be an important additional source that is relevant in PAD.

L-Lactate Dehydrogenase - metabolism

Up-Regulation

Intermittent Claudication - pathology

Peripheral Arterial Disease - pathology

Humans

Intermittent Claudication - drug therapy

Middle Aged

Caspase 1 - metabolism

Male

Muscle, Skeletal - metabolism

Intermittent Claudication - metabolism

Autophagy - drug effects

Case-Control Studies

HMGB1 Protein - genetics

Recovery of Function

Chloroquine - pharmacology

Ligation

HMGB1 Protein - metabolism

Muscle, Skeletal - drug effects

Female

Sequestosome-1 Protein - metabolism

Ischemia - pathology

Disease Models, Animal

Muscle, Skeletal - blood supply

HMGB1 Protein - deficiency

Peripheral Arterial Disease - metabolism

Cell Line

Mice, Inbred C57BL

Peripheral Arterial Disease - drug therapy

Ischemia - metabolism

Regional Blood Flow

Mice, Knockout

Animals

Ischemia - drug therapy

Signal Transduction - drug effects

Blood Flow Velocity

Aged

Muscle, Skeletal - pathology

Femoral Artery - surgery

Details

Title: Subtitle: Chloroquine improves the response to ischemic muscle injury and increases HMGB1 after arterial ligation
Creators: Jun Xu - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
Xiangdong Cui - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
Jiehua Li - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
Panagiotis Koutakis - Department of Surgery, University of Nebraska Medical Center, Omaha, Neb
Iraklis Pipinos - Department of Surgery, University of Nebraska Medical Center, Omaha, Neb
Edith Tzeng - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa; Department of Veterans Affairs, Pittsburgh, Pa
Alex Chen - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa
Ulka Sachdev - Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa. Electronic address: sachdevu2@upmc.edu
Resource Type: Journal article
Publication Details: Journal of vascular surgery, Vol.67(3), pp.910-921
DOI: 10.1016/j.jvs.2017.01.021
PMID: 28259568
PMCID: PMC5581296
NLM abbreviation: J Vasc Surg
ISSN: 0741-5214
eISSN: 1097-6809
Publisher: United States
Grant note: K08 HL103899 / NHLBI NIH HHS T32 HL098036 / NHLBI NIH HHS R01 AG034995 / NIA NIH HHS
Language: English
Date published: 03/2018
Academic Unit: Surgery
Record Identifier: 9984051886502771

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