Attenuation of cardiac dysfunction by HSPA12B in endotoxin-induced sepsis in mice through a PI3K-dependent mechanism.
OBJECTIVE
cardiac dysfunction is a critical manifestation of severe sepsis/septic shock and is responsible for high mortality due to sepsis. Recent evidence suggests that angiogenic factors have a protective effect on sepsis-induced organ damage. Heat shock protein A12B (HSPA12B) is a newly discovered gene that is essential for angiogenesis. We hypothesized that overexpression of HSPA12B would induce protection against endotoxin-induced cardiac dysfunction.


RESULTS
to evaluate this hypothesis, we generated transgenic mice overexpressing the human hspa12b gene (Tg). Wild-type (WT) littermates served as controls. Tg and WT mice were treated with lipopolysaccharide (LPS) and cardiac function was measured after 6 h. LPS treatment caused cardiac dysfunction in WT mice. In contrast, cardiac function was significantly preserved in Tg mice following LPS administration. LPS increased the expression of vascular cell adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1) and leucocyte infiltration into the myocardium of WT mice. In Tg mice, LPS-increased VCAM-1/ICAM-1 expression and leucocyte infiltration were significantly attenuated. Overexpression of HSPA12B also prevented the decrement in the activation of phosphatidlyinositide 3-kinase (PI3K)/protein kinase B (Akt) signalling in the myocardium. Importantly, PI3K inhibition with Wortmannin abolished the protection of HSPA12B against LPS-induced cardiac dysfunction.


CONCLUSIONS
these results suggest that HSPA12B plays an important role in the attenuation of endotoxin-induced cardiac dysfunction and that the mechanisms involve the preserved activation of PI3K/Akt signalling, resulting in attenuation of LPS-increased expression of VCAM-1/ICAM-1 and leucocyte infiltration into the myocardium.
Zhou
Hongmei
H
Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Qian
Jin
J
Li
Chuanfu
C
Li
Jingjin
J
Zhang
Xiaojin
X
Ding
Zhengnian
Z
Gao
Xiang
X
Han
Zhihua
Z
Cheng
Yunlin
Y
Liu
Li
L
D042683:Angiopoietin-1 / Q000378:metabolism; D000818:Animals; D019446:Endotoxemia / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000502:physiology*; D006331:Heart Diseases / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D042683:Angiopoietin-1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018840:HSP70 Heat-Shock Proteins; D020672:I-kappa B Proteins; D018799:Intercellular Adhesion Molecule-1; D008070:Lipopolysaccharides; D000072000:NF-KappaB Inhibitor alpha; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; C467628:Angpt1 protein, mouse; C472131:HSPA12B protein, human; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse