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Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction.

ABSTRACT: It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll-like receptors (TLRs) that respond to pathogen- and damage-associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4-mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax ) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4-blocking antibodies. We conclude that the expression, ligand-binding capacity and pro-inflammatory function of cardiomyocyte TLR4 are up-regulated after long-term MI, which promote inflammation and exacerbate heart failure.

SUBMITTER: Liu L

PROVIDER: S-EPMC4687701 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction.

Liu Li L Wang Yin Y Cao Zhi-Yong ZY Wang Meng-Meng MM Liu Xue-Mei XM Gao Ting T Hu Qi-Kuan QK Yuan Wen-Jun WJ Lin Li L

Journal of cellular and molecular medicine 20150820 12

It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll-like receptors (TLRs) that respond to pathogen- and damage-associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4-mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and functi ...[more]

PMID: 26290459

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Project description:AimsSarcolipin (SLN) is a key regulator of sarcoplasmic reticulum calcium-ATPase (SERCA)2a, which handles intracellular calcium re-uptake. This study was aimed to investigate the involvement of SLN in post-myocardial infarction (MI) heart failure (HF) in diabetes.Methods and resultsDiabetes/MI rat models were established. Altered SLN expression in diabetic hearts was screened out by microarray. A myocardiotropic viral vector was used to deliver siRNA to silence SLN. DNA methylation was evaluated by bisulfite sequencing. Cardiac functions were evaluated by invasive haemodynamic examinations. The SERCA2a activity, cytoplasmic calcium concentration ([Ca2+ ]i ), calcium spark, and myocyte contraction were detected. Correlation between HF and diabetes was analysed in a cohort consisted of 101 ST-segment elevated myocardial infarction (STEMI) patients between 2017 and 2019 [53.54 ± 4.64 years old; 61.4% male gender; HbA1c% 6.15 ± 2.00; and left ventricular ejection fraction (LVEF%) 40.64 ± 3.20%]. SLN expression was evaluated in left ventricular tissue sample from six STEMI patients complicated with diabetes and six STEMI patients without diabetes. Expressions of DNA methyltransferase 1a and DNA methyltransferase 3 were reduced in diabetic hearts, leading to down-regulation of SLN promoter methylation, resulting in increased SLN expression in rats. Impaired heart systolic functions were found in experimental diabetic MI rats, which were attenuated by SLN silencing. SERCA2a activity reduction and [Ca2+ ]i elevation were attenuated by SLN silencing in diabetic animal hearts and high-glucose incubated primary myocytes. SLN silencing suppressed calcium sparks and improved contraction and sarcoplasmic reticulum calcium re-uptake in high-glucose incubated primary myocytes. Expression of SLN was up-regulated in LV sampled from STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.05). LVEF% was reduced in STEMI patients complicated with diabetes compared with non-diabetic ones (P < 0.01). HbA1c% and LVEF% was related (r = -0.218, P = 0.028). Increased HbA1c% was correlated with reduced LVEF% after adjustment for age, sex, body mass index, cigarette smoking, creatinine, UA, low density lipoprotein, K+ , Na+ , and troponin I (adjusted odds ration = 0.75, 95% confidence interval 0.62-0.90, P = 0.002).ConclusionsDiabetes increases the vulnerability of STEMI patients to post-MI HF by down-regulating SLN promoter methylation, which further regulates SERCA2a activity via increasing cardiac SLN expression.

Project description:BackgroundAlthough silent myocardial infarction (SMI) accounts for about one-half of the total number of myocardial infarctions (MIs), the risk of heart failure (HF) among patients with SMI is not well established.ObjectivesThe purpose of this study was to examine the association of SMI and clinically manifested myocardial infarction (CMI) with HF, as compared with patients with no MI.MethodsThis analysis included 9,243 participants from the ARIC (Atherosclerosis Risk In Communities) study who were free of cardiovascular disease at baseline (ARIC visit 1: 1987 to 1989). SMI was defined as electrocardiographic evidence of MI without CMI after the baseline until ARIC visit 4 (1996 to 1998). HF events were ascertained starting from ARIC visit 4 until 2010 in individuals free of HF before that visit.ResultsBetween ARIC visits 1 and 4, 305 SMIs and 331 CMIs occurred. After ARIC visit 4 and during a median follow-up of 13.0 years, 976 HF events occurred. The incidence rate of HF was higher in both CMI and SMI participants than in those without MI (incidence rates per 1,000 person-years were 30.4, 16.2, and 7.8, respectively; p < 0.001). In a model adjusted for demographics and HF risk factors, both SMI (hazard ratio [HR]: 1.35; 95% confidence interval [CI]: 1.02 to 1.78) and CMI (HR: 2.85; 95% CI: 2.31 to 3.51) were associated with increased risk of HF compared with no MI. These associations were consistent in subgroups of participants stratified by several HF risk predictors. However, the risk of HF associated with SMI was stronger in those younger than the median age (53 years) (HR: 1.66; 95% CI: 1.00 to 2.75 vs. HR: 1.19; 95% CI: 0.85 to 1.66, respectively; overall interaction p by MI type <0.001).ConclusionsSMI is associated with an increased risk of HF. Future research is needed to examine the cost effectiveness of screening for SMI as part of HF risk assessment, and to identify preventive therapies to improve the risk of HF among patients with SMI.

Project description:AimsNew-onset atrial fibrillation (NOAF) complicating acute myocardial infarction (AMI) has been associated with poor survival, but the clinical implication of NOAF on heart failure (HF) is still not well characterized. We aimed to investigate the relationship between NOAF complicating AMI and HF hospitalization.Methods and resultsAdult AMI patients identified in the New-Onset Atrial Fibrillation Complicating Acute Myocardial Infarction in Shanghai registry who, discharged alive, had complete echocardiography and follow-up data from February 2014 to March 2018 were included. Patients were divided according to the presence of NOAF. The outcome measures were HF hospitalization and death during the observational period (until 10 April 2019). Cox proportional hazard models were performed in the whole population and propensity score-matched (PSM) cohort to assess the adjusted hazard ratio (HR) and 95% confidence interval (CI). Overall, 2075 patients (mean age: 65.2 ± 12.3 years, 77.3% were men) with AMI were analysed, of whom 228 (11.0%) developed NOAF. Advanced age, admission HF (Killip II-IV), impaired renal function, decreased left ventricular ejection fraction, increased heart rate, and left atrial enlargement were independent predictors of NOAF. Over a median observational period of 2.7 years, the annual incidence rates of HF hospitalization were 18.4% and 2.8% for patients with NOAF and sinus rhythm, respectively. After adjustment for confounders, NOAF was significantly associated with HF hospitalization (HR: 3.14, 95% CI: 2.30-4.28, P < 0.001). Similar results were obtained when accounting for the competing risk of all-cause death (subdistribution HR: 3.06, 95% CI: 2.18-4.30, P < 0.001) or from the PSM cohort (HR: 2.82, 95% CI: 1.99-4.00, P < 0.001). Patients with persistent NOAF (HR: 5.81, 95% CI: 3.59-9.41) were at significantly higher risk of HF hospitalization when compared with those with transient one (HR: 2.61, 95% CI: 1.84-3.70, P interaction = 0.008). Although post-MI NOAF was significantly related to cardiovascular death (annual incidence rates for NOAF and sinus rhythm were 9.4% and 2.3%, respectively; HR: 1.97, 95% CI: 1.36-2.85, P < 0.001), such an association was attenuated when HF hospitalization (modelled as a time-varying covariate) and antithrombotic treatment were adjusted (HR: 1.37, 95% CI: 0.92-2.02, P = 0.121).ConclusionsIn patients with AMI, NOAF is strongly associated with an increased long-term risk of HF hospitalization. Our findings suggest that strengthened secondary prevention of HF should be considered in this high-risk population.

Dataset Information

Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction.

Publications

Up-regulated TLR4 in cardiomyocytes exacerbates heart failure after long-term myocardial infarction.

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