Key result
TLR4 activation by LPS promotes cardiac inflammation, mitochondrial dysfunction, apoptosis, and fibrosis through SIRT2-dependent p53 deacetylation.
Why the study?
Activation of TLR4 causes cardiac hypertrophy and injury, but the precise mechanism of TLR4-mediated adverse cardiac outcomes remains elusive.
Does TLR4 activation promote cardiomyocyte apoptosis and fibrosis in rat models and H9c2 cells?
Does TLR4 activation promote cardiomyocyte apoptosis and fibrosis in rat models and H9c2 cells?
TLR4 activation promotes cardiac inflammation, mitochondrial dysfunction, apoptosis, and fibrosis via SIRT2-dependent p53 acetylation, suggesting TLR4 as a potential therapeutic target for heart failure.
Answers are grounded in this paper and cite their sources.
TLR4 inhibition merits testing in experimental HF models; leaves open whether SIRT2-p53 acetylation drives human disease.
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.
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Katare et al. (2020) studied Cardiac inflammation and apoptosis. Lipopolysaccharide (LPS) vs. Pyrogen-free saline was evaluated on Cardiac apoptosis, fibrosis, and mitochondrial dysfunction (p=<0.05). TLR4 activation by LPS promotes cardiac inflammation, mitochondrial dysfunction, apoptosis, and fibrosis through SIRT2-dependent p53 deacetylation.
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