Fatty acid-binding protein 4 silencing protects against lipopolysaccharide-induced cardiomyocyte hypertrophy and apoptosis by inhibiting the Toll-like receptor 4–nuclear factor-κB pathway

Abstract

Objective To explore the effects and potential mechanisms of fatty acid-binding protein 4 (FABP4) in a lipopolysaccharide (LPS)-induced in vitro septic cardiomyopathy model. Methods Rat cardiomyocyte H9c2 cells were transfected with small interfering RNA (siRNA) against FABP4 (siFABP4), then induced with LPS. The following parameters were measured: cell viability, lactate dehydrogenase release, cardiac hypertrophy and related marker expression, apoptosis, inflammatory cytokine release and expression, and the activation of Toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) pathways. Results LPS increased the mRNA and protein expression of FABP4 in H9c2 cells. FABP4 silencing by siFABP4 significantly inhibited LPS-induced cardiac hypertrophy and reduced the mRNA expression of the myocardial hypertrophy markers atrial natriuretic peptide and brain natriuretic peptide. siFABP4 also attenuated LPS-induced increase in TUNEL-positive apoptotic cells, caspase-3 and caspase-9 activities, and the release and expression of proinflammatory cytokines. Mechanistically, we found that FABP4 silencing inhibited the mRNA and protein expression of TLR4 and suppressed the NF-kappa B signaling pathway, as evidenced by reduced nuclear NF-κB p65 and increased cytoplasmic I-κBα expression in LPS-stimulated H9c2 cells. Conclusion FABP4 silencing reduces LPS-induced cardiomyocyte hypertrophy and apoptosis by down-regulating the TLR4/NF-κB axis.

Cardiomyocyte-specific deletion of TLR4 attenuates angiotensin II-induced hypertension and cardiac remodeling

“…In this study, we build upon these findings and focus specifically on TLR4 inhibition in cardiomyocytes, the major contractile cells of the heart in Ang II-induced hypertension. TLR4 has been previously shown by our laboratory and others to be expressed in the heart (1,12,17,40). To confirm these findings in Ang II-induced hypertension, we measured TLR4 gene and protein expression in the heart and showed a significant elevation in TLR4.…”

Toll-like receptors in cardiac hypertrophy

“…Inhibiting some nucleic acid molecules, such as lncRNA CTPB1-AS2, lncRNA NEAT1 and miR-93, can ameliorate cardiac hypertrophy by downregulating TLR4 signaling ( 57 – 119 ). Silencing of protein molecule-like fatty acid-binding protein 4 protects against LPS-induced cardiomyocyte hypertrophy and apoptosis by inhibiting the TLR4/NF-κB pathway ( 120 ). Besides, CaMKII δ B silencing prevents cardiac hypertrophy independent of an inflammatory response by inhibiting the complement system and TLR2/4 NF-kB signaling ( 121 ).…”

Fatty Acid-Binding Proteins: Their Roles in Ischemic Stroke and Potential as Drug Targets

“…For example, FABP4 has been demonstrated to exacerbate I/R injury in mouse kidney tissue by modulating glucose-regulated protein 78 (GRP78)/C/EBP homologous protein (CHOP)/caspase-12 signaling to induce ER stress [ 92 ], whereas in a cellular I/R model, the involvement of FABP4 in endoplasmic reticulum stress has been found to be mediated via the PPARγ [ 102 ] and PI3K/Akt [ 103 ] pathways. As an important mediator of the inflammatory response, FABP4 is known to promote inflammation via mitochondrial uncoupling protein 2 (UCP2) [ 104 , 105 ], Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB) signaling [ 106 , 107 ]. Furthermore, following myocardial I/R, FABP4 knockout mice have been observed to have lower levels of myocardial infarct volume, inflammation, and oxidative and nitrative stress than wild-type mice [ 88 ], whereas the FABP4 inhibitor BMS309403 has been found to restore palmitic acid-induced mitochondrial dysfunction, including impaired respiratory complex IV and succinate dehydrogenase activity, and reduced mitochondrial membrane potential [ 108 ].…”