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

Yangchen Dhondup,Arne Yndestad,Muhammad Shakil Ahmed,Pål Aukrust,Alexandra Vanessa Finsen,Geir Christensen,Katrine Alfsnes,Øystein Sandanger,Jan Magnus Aronsen,Lili Zhang,Leif Erik Vinge,Ivar Sjaastad,Håvard Attramadal,Trine Ranheim

doi:10.1155/2017/9450439

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.

Highlights

Even with significant clinical improvements in the treatment of HF over the last decades, heart failure (HF) is a growing global challenge with a prevalence of over 23 million worldwide [1, 2]
Using this HF model, we demonstrated that chronic exposure to systemic toll-like receptor 9 (TLR9) stimulations aggravated diastolic HF [14]
Of the 52 animals in the combined survival study (WT, n = 7; TLR9 KO, n = 3; SERCA2a KO, n = 22; and SERCA2a/TLR9 KO, n = 20), 16 animals were euthanized due to objective prespecified criteria of distress indicating severe HF (SERCA2a KO, n = 6; SERCA2a/TLR9 KO, n = 10) and 26 animals died spontaneously (SERCA2a KO, n = 16; SERCA2a/TLR9 KO, n = 10). When including both euthanized and spontaneous deaths, we found reduced life expectancy in SERCA2a KO mice in the absence of TLR9 compared with that in SERCA2a KO mice (Figure 1(a))

Summary

Introduction

Even with significant clinical improvements in the treatment of HF over the last decades, heart failure (HF) is a growing global challenge with a prevalence of over 23 million worldwide [1, 2]. The treatment successes are restricted to HF with reduced ejection fraction (HF-REF). No HF-specific prognosis-altering intervention can be offered to patients suffering HF with preserved ejection fraction (HF-PEF) [3]. For HF as a whole, it is widely recognized that numerous cardiac molecular signalling systems are pathologically altered. Mediators of Inflammation strategies as of today target neurohormonal activation. Targeting of signalling systems beyond the neurohormonal axis may be of importance to improve HF treatment

Methods

Results

Conclusion