Toll-Like Receptor 9 Promotes Survival in SERCA2a KO Heart Failure Mice

Abstract

Aim. Inflammation is important in heart failure (HF). The role of the immune receptor toll-like receptor 9 (TLR9) in HF is not understood and not investigated in diastolic HF. We investigated the role of TLR9 in a murine diastolic HF model caused by cardiomyocyte SERCA2a excision. Methods and Results. We crossed SERCA2a KO and TLR9 KO mice to generate four mouse lines. Tamoxifen-induced cardiomyocyte SERCA2a gene excision was carried out in mice, causing diastolic HF. After 7.6 weeks, cardiac functions and dimensions were analyzed by echocardiography and heart tissues were processed. HF mice depleted of TLR9 demonstrated reduced survival compared to SERC2a KO mice, with a median life expectancy of 58 days compared to 63 days. Both HF groups displayed increased left atrium size, lung weight, fetal gene expressions, monocyte/macrophage infiltration, and fibrosis. However, there were no significant differences between the groups. Conclusion. In mice with SERCA2a KO-induced diastolic HF, the absence of TLR9 reduced median life expectancy. The cause remains elusive, as all investigated HF parameters were unaltered. Still, these findings support a salutary role of TLR9 in some subsets of HF conditions and underline the importance for future studies on the mechanisms of TLR9 in diastolic HF.

The Role of Toll-Like Receptor Signaling in the Progression of Heart Failure

“…Dhondup et al [ 94 ] reported that in a mouse model with diastolic HF caused by cardiomyocyte-specific deletion of SERCA2a, sustained activation of TLR9 caused cardiac and systemic inflammation and deterioration of SERCA2a depletion-mediated diastolic HF. In another diastolic HF mouse model induced by cardiomyocyte-specific deletion of SERCA2a, TLR9 depletion in those models reduced the survival rate compared with that of the SERCA2a KO control mice; this finding indicates the salutary role of TLR9 in some subsets of HF [ 95 ]. These studies suggest a link between systemic TLR9 activation and diastolic HF.…”

MAIR‐II deficiency ameliorates cardiac remodelling post‐myocardial infarction by suppressing TLR9‐mediated macrophage activation

“…28 Moreover, the role of TLR9 has been implicated in several animal studies of cardiovascular diseases including myocardial infarction, [29][30][31] myocardial ischaemia/reperfusion injury, 32 atherosclerosis 33,34 and heart failure. 35,36 Elevated plasma levels of mtDNA have also been reported in patient studies associated with increased mortality and cardiac inflammation. 20,37 In our study, the amount of circulating mtDNA increased following MI and lower pro-inflammatory cytokine expression was observed in MAIR-II-deficient BMDMs stimulated by a TLR9 agonist.…”

“…Once NF‐κB is activated, pro‐inflammatory cytokine transcription is up‐regulated 28 . Moreover, the role of TLR9 has been implicated in several animal studies of cardiovascular diseases including myocardial infarction, 29‐31 myocardial ischaemia/reperfusion injury, 32 atherosclerosis 33,34 and heart failure 35,36 . Elevated plasma levels of mtDNA have also been reported in patient studies associated with increased mortality and cardiac inflammation 20,37 .…”

TLR9 Binding to Beclin 1 and Mitochondrial SIRT3 by a Sodium-Glucose Co-Transporter 2 Inhibitor Protects the Heart from Doxorubicin Toxicity

“…TLR9 can also prevent cardiac rupture after myocardial infarction [33]. Knockout of TLR9 in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) diastolic heart failure mice reduces their survival [34]. However, ablation of TLR9 in mice attenuates myocardial ischemia injury [35].…”