Tolerogenic dendritic cells induced by atorvastatin via inhibition of the TLR-4/NF-κB pathway improve cardiac remodeling after myocardial infarction

Abstract BackgroundNecrosis of ischemic cardiomyocytes after myocardial infarction (MI) activates an intense inflammatory reaction. Dendritic cells (DCs) play a crucial role in the repair process after MI. Tolerogenic DCs (tDCs) can inhibit inflammatory responses. Methods and resultsWe investigated the role of atorvastatin and supernatants of necrotic cardiomyocytes (SNC) on DCs. We found that SNC induced DCs maturation, activated TLR-4/NF-κB pathway, promoted inflammatory cytokines secretion and oxidative stress. Co-treatment with SNC and atorvastatin suppressed DC maturation and inflammatory response, which meant that atorvastatin induced DCs tolerate to SNC. Then, we investigated the effect of mDCs induced by SNC and tDCs induced by atorvastatin on ventricular remodeling after MI. tDCs treatment significantly improved the left ventricular systolic function, reduced the infiltration of MPO+ neutrophil, Mac3+ macrophages and CD3+ T cells, inhibited myocardial apoptosis and fibrosis, and decreased infarct size. Compared with PBS, treatment with mDCs did not showed beneficial effect on ventricular remodeling and inflammatory reaction after MI in mice.ConclusionAtorvastatin inactivated the TLR-4/NF-κB pathway, repressed the oxidative stress, inflammatory response, and immune maturity induced by SNC. Treatment with tDCs, induced by co-treated with atorvastatin, preserved left ventricular function, limited infarct size, suppressed the infiltration of inflammatory cells, and attenuated the severity of fibrosis, and reduced the number of apoptotic cardiomyocytes.

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Implication of anti-angiogenic VEGF-A165b in angiogenesis and systolic function after reperfused myocardial infarction

European Heart Journal ◽

10.1093/ehjci/ehaa946.3645 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

V Marcos Garces ◽

C Rios-Navarro ◽

L Hueso ◽

A Diaz ◽

C Bonanad ◽

...

Keyword(s):

Myocardial Infarction ◽

Adjuvant Therapy ◽

Ejection Fraction ◽

Infarct Size ◽

Systolic Function ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Funding Source ◽

Coronary Reperfusion ◽

Ventricular Ejection Fraction

Abstract Background Angiogenesis participates in re-establishing microcirculation after myocardial infarction (MI). Purpose In this study, we aim to further understand the role of the anti-angiogenic isoform vascular endothelial growth factor (VEGF)-A165b after MI and explore its potential as a co-adjuvant therapy to coronary reperfusion. Methods Two mice MI models were formed: 1) permanent coronary ligation (non-reperfused MI), 2) transient 45-min coronary occlusion followed by reperfusion (reperfused MI); in both models, animals underwent echocardiography before euthanasia at day 21 after MI induction. Serum and myocardial VEGF-A165b levels were determined. In both experimental MI models, functional and structural implication of VEGF-A165b blockade was assessed. In a cohort of 104 ST-segment elevation MI patients, circulating VEGF-A165b levels were correlated with cardiovascular magnetic resonance-derived left ventricular ejection fraction at 6-months and with the occurrence of adverse events (death, heart failure and/or re-infarction). Results In both models, circulating and myocardial VEGF-A165b presence was increased 21 days after MI induction. Serum VEGF-A165b levels inversely correlated with systolic function evaluated by echocardiography. VEGF-A165b blockage increased capillary density, reduced infarct size, and enhanced left ventricular function in reperfused, but not in non-reperfused MI experiments. In patients, higher VEGF-A165b levels correlated with depressed ejection fraction and worse outcomes. Conclusions In experimental and clinical studies, higher serum VEGF-A165b levels associates with a worse systolic function. Its blockage enhances neoangiogenesis, reduces infarct size, and increases ejection fraction in reperfused, but not in non-reperfused MI experiments. Therefore, VEGF-A165b neutralization represents a potential co-adjuvant therapy to coronary reperfusion. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was funded by “Instituto de Salud Carlos III” and “Fondos Europeos de Desarrollo Regional FEDER” (Exp. PIE15/00013, PI17/01836, PI18/00209 and CIBERCV16/11/00486).

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Role of oxidative stress in left ventricular remodeling and heart failure after myocardial infarction

Journal of Cardiac Failure ◽

10.1016/s1071-9164(99)91277-0 ◽

1999 ◽

Vol 5 (3) ◽

pp. 79

Author(s):

Shintaro Kinugawa ◽

Hiroyuki Tsutsui ◽

Tomomi Ide ◽

Hideo Ustumi ◽

Nobuhiro Suematsu ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular

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Progression of heart failure after myocardial infarction in the rat

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.5.r1734 ◽

2001 ◽

Vol 281 (5) ◽

pp. R1734-R1745 ◽

Cited By ~ 111

Author(s):

J. Francis ◽

R. M. Weiss ◽

S. G. Wei ◽

A. K. Johnson ◽

R. B. Felder

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Ventricular Remodeling ◽

Systolic Function ◽

Left Ventricular Remodeling ◽

Plasma Renin ◽

Left Ventricular Systolic Function ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Artery Ligation

This study examined the early neurohumoral events in the progression of congestive heart failure (CHF) after myocardial infarction (MI) in rats. Immediately after MI was induced by coronary artery ligation, rats had severely depressed left ventricular systolic function and increased left ventricular end-diastolic volume (LVEDV). Both left ventricular function and the neurohumoral indicators of CHF underwent dynamic changes over the next 6 wk. LVEDV increased continuously over the study interval, whereas left ventricular stroke volume increased but reached a plateau at 4 wk. Plasma renin activity (PRA), arginine vasopressin, and atrial natriuretic factor all increased, but with differing time courses. PRA declined to a lower steady-state level by 4 wk. Six to 8 wk after MI, CHF rats had enhanced renal sympathetic nerve activity and blunted baroreflex regulation. These findings demonstrate that the early course of heart failure is characterized not by a simple “switching on” of neurohumoral drive, but rather by dynamic fluctuations in neurohumoral regulation that are linked to the process of left ventricular remodeling.

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