Activation of toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent p53 deacetylation

Abstract

Cardiomyocyte inflammation followed by apoptosis and fibrosis is an important mediator for development and progression of heart failure. Activation of toll-like receptor 4 (TLR4), an important regulator of inflammation, causes the progression of cardiac hypertrophy and injury. However, the precise mechanism of TLR4-mediated adverse cardiac outcomes is still elusive. The present study was designed to find the role of TLR4 in cardiac fibrosis and apoptosis, and molecular mechanism thereof. Rats were treated with TLR4 agonist (LPS 12.5 μg/kg/day) through osmotic pump for 14 days. To simulate the condition in vitro, H9c2 cells were treated with LPS (1 μg/ml). Similarly, H9c2 cells were transfected with TLR4 and SIRT2 c-DNA clone for overexpression. Myocardial oxidative stress, inflammation, fibrosis and mitochondrial parameters were evaluated both in vitro and in vivo. Cardiac inflammation after LPS treatment was confirmed by increased TNF-α and IL-6 expression in rat heart. There was a marked increase in oxidative stress as observed by increased TBARS and decreased endogenous antioxidants (GSH and catalase), along with mitochondrial dysfunction as measured by mitochondrial complex activity in LPS-treated rat hearts. Histopathological examination showed the presence of cardiac fibrosis after LPS treatment. Protein expression of nuclear p53 and cleaved caspase-7/caspase-9 was significantly increased in LPS treated heart. Similar to in vivo study, nuclear translocation of p53, mitochondrial dysfunction and cellular apoptosis were observed in H9c2 cells treated with LPS. Our data also indicate that decreased expression of SIRT2 was associated with increased acetylation of p53 after LPS treatment. In conclusion, TLR4 activation in rats promotes cardiac inflammation, mitochondrial dysfunction, apoptosis and fibrosis. p53 and caspase 7/caspase 9 were found to play an important role in TLR4-mediated apoptosis. Our data suggest that, reducing TLR4 mediated fibrosis and apoptosis could be a novel approach in the treatment of heart failure, keeping in the view the major role played by TLR4 in cardiac inflammation.

Exploring the cytotoxic mechanisms of Pediocin PA-1 towards HeLa and HT29 cells by comparison to known bacteriocins: Microcin E492, enterocin heterodimer and Divercin V41

“…Definitive support can be found in the same study, as the use of zZad-fmk (a general caspase inhibitor) inhibited the cytotoxic effect of Microcin. Caspase 3 activation has been linked to the activation of TLR-4 [ 36 ], therefore we are confident in our conclusion that Microcin must bind to TLR-4. Caspase 1 activation has been linked to the efflux of potassium ions, which activates the NLRC4 (nucleotide-binding oligomerization domain and leucine-rich repeat containing receptors) inflammasome pathway leading to the assembly of caspase 1 [ 37 ].…”

“…Divercin has previously been shown to have a similar homology to Pediocin whilst showing no anti-tumour properties towards HT29 cells [ 36 ]. Therefore, we performed sequence alignment and 3D modelling of Divercin V41 in order to try and understand why, despite the similar homology, one shows anti-tumour effects towards HT29 cells and not the other.…”

Exosomal circRNA as a novel potential therapeutic target for multiple myeloma-related myocardial damage

“…At present, TLR4 has been identified as a crucial regulator in cardiovascular disease. Studies have found that TLR4 activation in rats promotes cardiac inflammation, mitochondrial dysfunction, apoptosis and fibrosis [ 59 , 60 ]. In addition, the "glutamate receptor pathway" and "calcium ion pathway" were often identified in GO and KEGG analyses.…”

The role of SIRT2 in vascular‐related and heart‐related diseases: A review

“…The overexpression of SIRT2 can inhibit the acetylation of p53 and thus inhibit the damage of TLR4 to cardiomyocytes. 39 The reason why SIRT2 has these two opposite functions needs further research to discover.…”