Abstract
Heart failure (HF) is a leading cause of morbidity and mortality in the western world. Although optimal medical care and treatment is widely available, the prognosis of patients with HF is still poor.Toll-like receptors (TLRs) are important compartments of the innate immunity. Current studies have identified TLRs as critical mediators in cardiovascular diseases. In the present study, we investigated the involvement of TLRs and interferon (IFN) regulatory factors (IRFs) in different experimental HF models including viral myocarditis, myocardial ischemia, diabetes mellitus, and cardiac hypertrophy. In addition, we investigated for the first time comprehensive TLR and IRF gene and protein expression under basal conditions in murine and human cardiac tissue. We found that Tlr4, Tlr9 and Irf7 displayed highest gene expression under basal conditions, indicating their significant role in first-line defense in the murine and human heart. Moreover, induction of TLRs and IRFs clearly differs between the various experimental HF models of diverse etiology and the concomitant inflammatory status. In the HF model of acute viral-induced myocarditis, TLR and IRF activation displayed the uppermost gene expression in comparison to the remaining experimental HF models, indicating the highest amount of myocardial inflammation in myocarditis. In detail, Irf7 displayed by far the highest gene expression during acute viral infection. Interestingly, post myocardial infarction TLR and IRF gene expression was almost exclusively increased in the infarct zone after myocardial ischemia (Tlr2, Tlr3, Tlr6, Tlr7, Tlr9, Irf3, Irf7). With one exception, Irf3 showed a decreased gene expression in the remote zone post infarction. Finally, we identified Irf7 as novel cardiovascular stress-inducible factor in the pathologically stressed heart. These findings on TLR and IRF function in the inflamed heart highlight the complexity of inflammatory immune response and raise more interesting questions for future investigation.
Highlights
Heart failure (HF) is a leading cause of hospitalization and mortality in the western world [1]
Gene and protein expression of the plasma membrane localized Tlr1, Tlr2, Tlr4, Tlr5, Tlr6 the intracellular localized Tlr3, Tlr7, Tlr8, Tlr9, and the IFN regulatory factors Irf3 and Irf7 were systematically analyzed under basal conditions in murine and human cardiac tissue (Fig 1)
The causality of the different TLR4 gene expression has yet not been identified [23]. These findings suggest that Toll-like receptors (TLRs) and their downstream signaling are significantly involved in inflammatory conditions in advanced HF
Summary
Heart failure (HF) is a leading cause of hospitalization and mortality in the western world [1]. Despite the implementation of optimal medical care and management of the HF syndrome [2, 3], prevalence, morbidity, mortality, and costs are still rising [4, 5]. The growth of our elderly population with increased prevalence of comorbidities such as coronary artery disease (CAD), myocardial infarction, hypertension, and diabetes that predispose those patients to this multifactorial syndrome is expected to rise HF prevalence in the future [6]. Current treatment strategies primarily slow the progression of the multifactorial HF syndrome. There is an important need to develop new preventative and restorable therapy options [2, 3]. The development of new HF therapies needs testing of the accepted therapeutic strategies in proper small and large animal models of advanced HF [7, 8]. The development of the complex HF syndrome involves several pathophysiological processes including activation of the immune system as trigger of left ventricular (LV) dysfunction and adverse cardiac remodeling [9]
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