Overexpression of Human C-Reactive Protein Exacerbates Left Ventricular Remodeling in Diabetic Cardiomyopathy

Mano, Yoshinori; Anzai, Toshihisa; Kaneko, Hidehiro; Nagatomo, Yuji; Nagai, Toshiyuki; Anzai, Atsushi; Maekawa, Yuichiro; Takahashi, Toshiyuki; Meguro, Tomomi; Yoshikawa, Tsutomu; Fukuda, Keiichi

doi:10.1253/circj.cj-10-1199

Cited by 51 publications

(37 citation statements)

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“…The grades were as follows: 0, no inflammatory infiltrates; 1, small foci of inflammatory cells between myocytes; 2, larger foci of greater than 100 inflammatory cells; 3, involving greater than 10% per cross-section; 4, involving greater than 30% per cross-section. Alternatively, cardiac fibrosis was evaluated by sirius-red staining [50].…”

Section: Histopathologymentioning

confidence: 99%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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High-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been implicated in cardiovascular diseases. Dilated cardiomyopathy (DCM), one of the leading causes of heart failure, is often caused by coxsackievirus B3-triggered myocarditis and promoted by the post-infectious autoimmune process. Th17 cells, a novel CD4 1 T subset, may be important in the pathogenesis of autoimmune myocarditis. In the present study, we attempted to block HMGB1 function with a monoclonal antibody specific for HMGB1 B box and investigated the effects of the blockade on Th17 cells and experimental autoimmune myocarditis (EAM). After induction of EAM, HMGB1 protein levels were significantly elevated both in the heart and blood. Administration of an anti-HMGB1 B box mAb attenuated cardiac pathological changes and reduced the number of infiltrating inflammatory cells in the heart during EAM. These protective effects of HMGB1 blockade correlated with a reduced number of Th17 cells in local tissues and lower levels of IL-17 in the serum. Furthermore, in vitro, studies demonstrated that HMGB1 promoted Th17-cell expansion. Therefore, we speculate that HMGB1 blockade ameliorates cardiac pathological changes in EAM by suppressing Th17 cells.Key words: Dilated cardiomyopathy . Experimental myocarditis . HMGB1 . Th17 cells IntroductionHigh-mobility group box 1 (HMGB1), a non-histone nuclear protein, has been functionally characterized as an alarmin or damage-associated molecular pattern (DAMP) [1,2]. It is constitutively expressed in quiescent cells and stored in the nucleus [3]. HMGB1 is one of the most evolutionarily conserved proteins in eukaryotes, with 100% identity between mice and rats, and 99% identity between rodents and humans [3].HMGB1 has been shown to be involved in both infectious and non-infectious inflammatory disease [2,4]. HMGB1 is released into the extracellular milieu during cell apoptosis/death [5], and by macrophages and monocytes in response to cellular stress or injury [6]. HMGB1 binds to the endogenous receptor for advanced glycation endproducts [7], exogenous toll-like receptor 2/4/9 (TLR2/4/9) [8,9], and CD24/Siglec-10 [10], and induces the expression of proinammatory cytokines, chemokines, and adhesion molecules [3,6]. Although, HMGB1 was initially 3586thought to be a late mediator of sepsis, recent data also indicated that HMGB1 is associated with many other pathological conditions, such as autoimmune disease [11], cancer [12][13][14], trauma, ischemia-reperfusion injury [15,16], tissue repair and regeneration [17,18], and cardiovascular diseases [19]. Furthermore, HMGB1 has restorative effects on CD4 1 T-helper cell modulation [20].Dilated cardiomyopathy (DCM) is one of the leading causes of severe heart failure and the most common indication for heart transplantation. DCM is often caused by coxsackievirus B3-triggered myocarditis [21]. Experimental autoimmune myocarditis (EAM) is a mouse model of postinfectious myocarditis, characterized by inflammatory infiltration of the myocardium and cardiac myocyte ne...

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Section: Histopathologymentioning

confidence: 99%

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Sun

Zhou

et al. 2011

Eur J Immunol

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“…4 As a distinguishing feature of the disease, diabetic cardiomyopathy is characterized by chronic inflammation, myocardial damage secondary to a metabolic insult, reactive hypertrophy and intermediary fibrosis, structural and functional changes of the small coronary vessels, interference with the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy leading to heart failure. [5][6][7][8] Altered cardiac structure and function are commonly found in asymptomatic patients with type 2 DM, even in the absence of hypertension and coronary artery disease. Echocardiography, an excellent non-invasive and imaging modality, defines cardiac structure and function.…”

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confidence: 99%

Advanced Left Ventricular Diastolic Dysfunction in Uremic Patients With Type 2 Diabetes on Maintenance Hemodialysis

Hung

Lee

Chen

et al. 2012

Circ J

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Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp iabetic nephropathy ranks as the leading etiology of end-stage renal disease (ESRD) requiring hemodialysis. 1 Cardiovascular complications largely account for the morbidity and mortality among such patients. 2 More than the most common cardiovascular alteration in ESRD, left ventricular (LV) hypertrophy is also an independent risk factor for survival. 3 As is well known, patients with diabetes mellitus (DM) are more prone to LV hypertrophy, coronary heart disease and impaired LV function. 4 As a distinguishing feature of the disease, diabetic cardiomyopathy is characterized by chronic inflammation, myocardial damage secondary to a metabolic insult, reactive hypertrophy and intermediary fibrosis, structural and functional changes of the small coronary vessels, interference with the management of the metabolic cardiovascular load, and cardiac autonomic neuropathy leading to heart failure. 5-8Altered cardiac structure and function are commonly found in asymptomatic patients with type 2 DM, even in the absence of hypertension and coronary artery disease. Echocardiography, an excellent non-invasive and imaging modality, defines cardiac structure and function. Early studies showed that half of the diabetic patients with decreased myocardial diastolic function remained undiagnosed on conventional echocardiography. 9 This inability is attributed to echocardiographic subestimation of the degree of diastolic dysfunction of 60% in subjects with normal arterial blood pressure. Under-diagnosis of the diastolic dysfunction may also occur in ESRD patients on maintenance hemodialysis with DM. Recent studies using tissue Doppler imaging (TDI) have contributed to the evaluation of diastolic function.

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“…[1][2][3][4] Ischemic injury promotes myocardial infl ammation and pro-infl ammatory cytokines stimulate C-reactive protein (CRP) leading to cardiac remodeling with LV dysfunction as its clinical manifestation. 5,6) Yet, the mechanisms of LV dysfunction post-AMI remain poorly understood. Indeed, high-sensitivity CRP (hs-CRP) is a marker of inflammation activated early after AMI and is associated with LV dysfunction, and is predictive of worse clinical outcomes.…”

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confidence: 99%

“…The choice of type and dose of statin was left to the doctor's discretion. The statins prescribed were simvastatin (20,40, 80 mg), rosuvastatin (5, 10, 20 mg), pravastatin (5,10,20, 40 mg), pitavastatin (2 mg), lovastatin (20 mg), atorvastatin (10,20,40, 80 mg), and fl uvastatin (20,40, 80 mg). Study defi nitions and outcome measurement: Blood samples for baseline laboratory tests including hs-CRP were obtained in the emergency room before PCI.…”

mentioning

confidence: 99%

Effect of Statin Treatment in Patients With Acute Myocardial Infarction and Left Ventricular Systolic Dysfunction According to the Level of High-Sensitivity C-Reactive Protein

et al. 2014

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SummaryThe effects of statins on the prognosis of patients with left ventricular (LV) systolic dysfunction remain controversial. The aim of this study was to assess the effect of statin treatment on clinical outcomes in acute myocardial infarction (AMI) patients with LV systolic dysfunction. A total of 5,119 AMI patients with LV ejection fraction less than 50% on the initial echocardiogram were analyzed in the Korean Acute Myocardial Infarction Registry. The study population was divided into 4 groups according to the level of high sensitivity C-reactive protein (hs-CRP) and statin treatment: low hs-CRP (hs-CRP ≤ 2.0 mg/L) and high hs-CRP (hs-CRP > 2 mg/L) with or without statin therapy. We evaluated the incidence of major adverse cardiac events (MACEs) including cardiac death, reinfarction, target lesion revascularization, and coronary artery bypass grafting during a 12-month period in each group. Statin therapy did not signifi cantly prevent the MACEs in the low hs-CRP groups (with statin: 10.1% versus without statin: 12.0%, P = 0.249). In the high hs-CRP groups, however, the incidence of MACEs was signifi cantly decreased with statin treatment (with statin: 11.3%, without statin: 20.8%, P < 0.001). These fi ndings were consistently observed in all subgroups of the high-hs CRP group, including the subgroup with an LV ejection fraction less than 40%. In a multivariable logistic regression analysis of the high hs-CRP group, lack of statin therapy was a signifi cant predictor of MACE incidence (odds ratio: 1.573, 95% confi dence interval: 1.079-2.293, P = 0.018). The statin treatment was associated with better outcome in AMI and LV dysfunction patients with hs-CRP ≥ 2 mg/dL. (Int Heart J 2014; 55: 106-112)

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Overexpression of Human C-Reactive Protein Exacerbates Left Ventricular Remodeling in Diabetic Cardiomyopathy

Cited by 51 publications

References 58 publications

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17‐cell expansion

Advanced Left Ventricular Diastolic Dysfunction in Uremic Patients With Type 2 Diabetes on Maintenance Hemodialysis

Effect of Statin Treatment in Patients With Acute Myocardial Infarction and Left Ventricular Systolic Dysfunction According to the Level of High-Sensitivity C-Reactive Protein

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