{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T12:56:32Z","timestamp":1773665792018,"version":"3.50.1"},"reference-count":48,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2012,9,5]],"date-time":"2012-09-05T00:00:00Z","timestamp":1346803200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2012,10]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold> Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll\u2010like receptor 4 (TLR4) in anthrax lethal toxin\u2010induced cardiac contractile dysfunction.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold> Wild\u2010type (WT) and TLR4 knockout (TLR<jats:sup>\u2212\/\u2212<\/jats:sup>) mice were challenged with lethal toxin (2\u2003\u00b5g\u00b7g<jats:sup>\u22121<\/jats:sup>, i.p.), and cardiac function was assessed 18\u2003h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP\u2013LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline\u20101, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2\u03b1 and calreticulin).<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold> In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening\/re\u2010lengthening, prolonged re\u2010lengthening duration and intracellular Ca<jats:sup>2+<\/jats:sup> derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3\u2010methyladenine significantly attenuated or inhibited lethal toxin\u2010induced autophagy in H9C2 cells.<\/jats:p><jats:p><jats:bold>CONCLUSION AND IMPLICATIONS<\/jats:bold> Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection\u2010induced cardiovascular complications.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2012.02040.x","type":"journal-article","created":{"date-parts":[[2012,5,21]],"date-time":"2012-05-21T14:12:53Z","timestamp":1337609573000},"page":"612-626","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Expression of Concern: Toll\u2010like receptor 4 knockout protects against anthrax lethal toxin\u2010induced cardiac contractile dysfunction: role of autophagy"],"prefix":"10.1111","volume":"167","author":[{"given":"Machender R","family":"Kandadi","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arthur 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