Key result
TLR2 deficiency in mice subjected to chronic pressure overload resulted in less hypertrophy, increased contractility, and lower ventricular TLR4 mRNA levels (13.2 vs. 16.6 mg/mm, p<0.01).
Why the study?
The role of TLR2 and its interplay with TLR4 in adverse cardiac remodeling and heart failure during pressure overload were not investigated.
Does TLR2 deficiency reduce adverse cardiac remodeling upon chronic pressure overload in mice?
Does TLR2 deficiency reduce adverse cardiac remodeling upon chronic pressure overload in mice?
Absolute Event Rate: 13.2% vs 16.6%
p-value: p=<0.01
TLR2 deficiency ameliorates adverse cardiac remodeling during chronic pressure overload in mice, suggesting TLR2 and TLR4 as potential therapeutic targets.
May support TLR2 as target in pressure overload; leaves open translation to human HF.
Involvement of the Toll-like receptor 4 (TLR4) in maladaptive cardiac remodeling and heart failure (HF) upon pressure overload has been studied extensively, but less is known about the role of TLR2. Interplay and redundancy of TLR4 with TLR2 have been reported in other organs but were not investigated during cardiac dysfunction. We explored whether TLR2 deficiency leads to less adverse cardiac remodeling upon chronic pressure overload and whether TLR2 and TLR4 additively contribute to this. We subjected 35 male C57BL/6J mice (wildtype (WT) or TLR2 knockout (KO)) to sham or transverse aortic constriction (TAC) surgery. After 12 weeks, echocardiography and electrocardiography were performed, and hearts were extracted for molecular and histological analysis. TLR2 deficiency (n = 14) was confirmed in all KO mice by PCR and resulted in less hypertrophy (heart weight to tibia length ratio (HW/TL), smaller cross-sectional cardiomyocyte area and decreased brain natriuretic peptide (BNP) mRNA expression, p < 0.05), increased contractility (QRS and QTc, p < 0.05), and less inflammation (e.g., interleukins 6 and 1β, p < 0.05) after TAC compared to WT animals (n = 11). Even though TLR2 KO TAC animals presented with lower levels of ventricular TLR4 mRNA than WT TAC animals (13.2 ± 0.8 vs. 16.6 ± 0.7 mg/mm, p < 0.01), TLR4 mRNA expression was increased in animals with the largest ventricular mass, highest hypertrophy, and lowest ejection fraction, leading to two distinct groups of TLR2 KO TAC animals with variations in cardiac remodeling. This variation, however, was not seen in WT TAC animals even though heart weight/tibia length correlated with expression of TLR4 in these animals (r = 0.078, p = 0.005). Our data suggest that TLR2 deficiency ameliorates adverse cardiac remodeling and that ventricular TLR2 and TLR4 additively contribute to adverse cardiac remodeling during chronic pressure overload. Therefore, both TLRs may be therapeutic targets to prevent or interfere in the underlying molecular processes.
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Kessler et al. (2021) studied Adverse cardiac remodeling upon chronic pressure overload (n=35). TLR2 deficiency (knockout) vs. Wildtype (WT) was evaluated on Ventricular TLR4 mRNA levels (mg/mm) (p=<0.01). TLR2 deficiency in mice subjected to chronic pressure overload resulted in less hypertrophy, increased contractility, and lower ventricular TLR4 mRNA levels (13.2 vs. 16.6 mg/mm, p<0.01).
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