Abstract
AimCardiac inflammation is important in the pathogenesis of heart failure. However, the consequence of systemic inflammation on concomitant established heart failure, and in particular diastolic heart failure, is less explored. Here we investigated the impact of systemic inflammation, caused by sustained Toll-like receptor 9 activation, on established diastolic heart failure.Methods and ResultsDiastolic heart failure was established in 8–10 week old cardiomyocyte specific, inducible SERCA2a knock out (i.e., SERCA2a KO) C57Bl/6J mice. Four weeks after conditional KO, mice were randomized to receive Toll-like receptor 9 agonist (CpG B; 2μg/g body weight) or PBS every third day. After additional four weeks, echocardiography, phase contrast magnetic resonance imaging, histology, flow cytometry, and cardiac RNA analyses were performed. A subgroup was followed, registering morbidity and death. Non-heart failure control groups treated with CpG B or PBS served as controls. Our main findings were: (i) Toll-like receptor 9 activation (CpG B) reduced life expectancy in SERCA2a KO mice compared to PBS treated SERCA2a KO mice. (ii) Diastolic function was lower in SERCA2a KO mice with Toll-like receptor 9 activation. (iii) Toll-like receptor 9 stimulated SERCA2a KO mice also had increased cardiac and systemic inflammation.ConclusionSustained activation of Toll-like receptor 9 causes cardiac and systemic inflammation, and deterioration of SERCA2a depletion-mediated diastolic heart failure.
Highlights
Heart failure (HF) is a major cause of morbidity and mortality worldwide with an overall prevalence of about 2–3% [1]
Diastolic heart failure was established in 8–10 week old cardiomyocyte specific, inducible SERCA2a knock out (i.e., SERCA2a KO) C57Bl/6J mice
Our main findings were: (i) Toll-like receptor 9 activation (CpG B) reduced life expectancy in SERCA2a KO mice compared to PBS treated SERCA2a KO mice. (ii) Diastolic function was lower in SERCA2a KO mice
Summary
Heart failure (HF) is a major cause of morbidity and mortality worldwide with an overall prevalence of about 2–3% [1]. Major improvements have been made in the management of HF, there is still an imminent need for novel treatment strategies. More knowledge of the pathogenic mechanisms is needed including identification of central pathogenic molecular players involved in the development and progression of this disorder. Activation of the innate immune system is an important pathogenic mechanism in HF [2,3,4]. The innate immune system consists of pattern recognition receptors (PRRs) that are activated by evolutionary conserved microbial structures denominated pathogen associated molecular patterns (PAMPs). PRRs recognize self-antigens i.e., damage associated molecular patterns (DAMPs), which are released upon cellular stress or death [5]. Upon PRR activation, a robust inflammatory response is seen with the induction of a plethora of cytokines and adhesion molecules and subsequent mobilization of leukocytes into inflamed tissue [6]
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