Ezh2 emerges as an epigenetic checkpoint regulator during monocyte differentiation limiting cardiac dysfunction post-MI.

Epigenetic regulation of histone H3K27 methylation has recently emerged as a key step during alternative immunoregulatory M2-like macrophage polarization; known to impact cardiac repair after Myocardial Infarction (MI). We hypothesized that EZH2, responsible for H3K27 methylation, could act as an epigenetic checkpoint regulator during this process. We demonstrate for the first time an ectopic EZH2, and putative, cytoplasmic inactive localization of the epigenetic enzyme, during monocyte differentiation into M2 macrophages in vitro as well as in immunomodulatory cardiac macrophages in vivo in the post-MI acute inflammatory phase.

CRISPR/Cas9-mediated inactivation of the phosphatase activity of soluble epoxide hydrolase prevents obesity and cardiac ischemic injury.

Introduction: Although the physiological role of the C-terminal hydrolase domain of the soluble epoxide hydrolase (sEH-H) is well investigated, the function of its N-terminal phosphatase activity (sEH-P) remains unknown.

Objectives: This study aimed to assess in vivo the physiological role of sEH-P.

Methods: CRISPR/Cas9 was used to generate a novel knock-in (KI) rat line lacking the sEH-P activity.

Regulation and impact of cardiac lymphangiogenesis in pressure-overload-induced heart failure.

Aims: Lymphatics are essential for cardiac health, and insufficient lymphatic expansion (lymphangiogenesis) contributes to development of heart failure (HF) after myocardial infarction. However, the regulation and impact of lymphangiogenesis in non-ischaemic cardiomyopathy following pressure-overload remains to be determined. Here, we investigated cardiac lymphangiogenesis following transversal aortic constriction (TAC) in C57Bl/6 and Balb/c mice, and in end-stage HF patients.

Mineralocorticoid receptor blockade with finerenone improves heart function and exercise capacity in ovariectomized mice.

Aims: In post-menopausal women, incidence of heart failure with preserved ejection fraction is higher than in men. Hormonal replacement therapies did not demonstrate benefits. We tested whether the non-steroidal mineralocorticoid receptor antagonist finerenone limits the progression of heart failure in ovariectomized (OVX) mice with metabolic disorders.

Lymphatic and Immune Cell Cross-Talk Regulates Cardiac Recovery After Experimental Myocardial Infarction.

Objective: Lymphatics play an essential pathophysiological role in promoting fluid and immune cell tissue clearance. Conversely, immune cells may influence lymphatic function and remodeling. Recently, cardiac lymphangiogenesis has been proposed as a therapeutic target to prevent heart failure after myocardial infarction (MI).

Myocardial Injury After Ischemia/Reperfusion Is Attenuated By Pharmacological Galectin-3 Inhibition.

Although optimal therapy for myocardial infarction includes reperfusion to restore blood flow to the ischemic region, ischemia/reperfusion (IR) also initiates an inflammatory response likely contributing to adverse left ventricular (LV) extracellular matrix (ECM) remodeling. Galectin-3 (Gal-3), a β-galactoside-binding-lectin, promotes cardiac remodeling and dysfunction. Our aim is to investigate whether Gal-3 pharmacological inhibition using modified citrus pectin (MCP) improves cardiac remodeling and functional changes associated with IR.

The IL-1β Antibody Gevokizumab Limits Cardiac Remodeling and Coronary Dysfunction in Rats With Heart Failure.

This study reports preclinical data showing that the interleukin (IL)-1β modulation is a new promising target in the pathophysiological context of heart failure. Indeed, in nondiabetic Wistar and diabetic Goto-Kakizaki rats with chronic heart failure induced by myocardial infarction, administration of the IL-1β antibody gevokizumab improves 'surrogate' markers of survival (i.e.

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure.

Background: Chronic heart failure (CHF) induces endothelial dysfunction in part because of decreased nitric oxide (NO(·)) production, but the direct link between endothelial dysfunction and aggravation of CHF is not directly established. We previously reported that increased NO production via inhibition of protein tyrosine phosphatase 1B (PTP1B) is associated with reduced cardiac dysfunction in CHF. Investigation of the role of endothelial PTP1B in these effects may provide direct evidence of the link between endothelial dysfunction and CHF.

Selective Stimulation of Cardiac Lymphangiogenesis Reduces Myocardial Edema and Fibrosis Leading to Improved Cardiac Function Following Myocardial Infarction.

Background: The lymphatic system regulates interstitial tissue fluid balance, and lymphatic malfunction causes edema. The heart has an extensive lymphatic network displaying a dynamic range of lymph flow in physiology. Myocardial edema occurs in many cardiovascular diseases, eg, myocardial infarction (MI) and chronic heart failure, suggesting that cardiac lymphatic transport may be insufficient in pathology.

Vascular Smooth Muscle Mineralocorticoid Receptor Contributes to Coronary and Left Ventricular Dysfunction After Myocardial Infarction.

Mineralocorticoid receptor (MR) antagonists slow down the progression of heart failure after myocardial infarction (MI), but the cell-specific role of MR in these benefits is unclear. In this study, the role of MR expressed in vascular smooth muscle cells (VSMCs) was investigated. Two months after coronary artery ligation causing MI, mice with VSMC-specific MR deletion (MI-MR(SMKO)) and mice treated with the MR antagonist finerenone (MI-fine) had improved left ventricular compliance and elastance when compared with infarcted control mice (MI-CTL), as well as reduced interstitial fibrosis.

Selective Heart Rate Reduction Improves Metabolic Syndrome-related Left Ventricular Diastolic Dysfunction.

Background: Enhanced heart rate observed in metabolic syndrome (MS) contributes to the deterioration of left ventricular (LV) function via impaired LV filling and relaxation, increased myocardial O2 consumption, and reduced coronary perfusion. However, whether heart rate reduction (HRR) opposes LV dysfunction observed in MS is unknown.

Methods: We assessed in Zucker fa/fa rats, a rat model of MS, the cardiovascular effects of HRR induced by the If current inhibitor S38844 (3 mg · kg(-1) · d(-1)).

Role of M2-like macrophage recruitment during angiogenic growth factor therapy.

Therapeutic angiogenesis has yet to fulfill its promise for the clinical treatment of ischemic diseases. Given the impact of macrophages during pathophysiological angiogenesis, we asked whether macrophages may similarly modulate vascular responses to targeted angiogenic therapies. Mouse matrigel plug assay and rat myocardial infarction (MI) model were used to assess angiogenic therapy with either VEGF-A or FGF-2 with HGF (F+H) delivered locally via albumin-alginate microcapsules.

Enhanced angiogenesis and increased cardiac perfusion after myocardial infarction in protein tyrosine phosphatase 1B-deficient mice.

The protein tyrosine phosphatase 1B (PTP1B) modulates tyrosine kinase receptors, among which is the vascular endothelial growth factor receptor type 2 (VEGFR2), a key component of angiogenesis. Because PTP1B deficiency in mice improves left ventricular (LV) function 2 mo after myocardial infarction (MI), we hypothesized that enhanced angiogenesis early after MI via activated VEGFR2 contributes to this improvement. At 3 d after MI, capillary density was increased at the infarct border of PTP1B(-/-) mice [+7±2% vs.

Gene deletion of protein tyrosine phosphatase 1B protects against sepsis-induced cardiovascular dysfunction and mortality.

Objective: Cardiovascular dysfunction is a major cause of mortality in patients with sepsis. Recently, we showed that gene deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) improves endothelial dysfunction and reduces the severity of experimental heart failure. However, the cardiovascular effect of PTP1B invalidation in sepsis is unknown.

Circulating plasma serine208-phosphorylated troponin T levels are indicator of cardiac dysfunction.

Heart failure (HF) following myocardial infarction (MI) is characterized by progressive alterations of left ventricular (LV) structure and function, named LV remodelling. Although several risk factors such as infarct size have been identified, HF remains difficult to predict in clinical practice. Recently, using phosphoproteomic technology, we found that serine(208)-phosphorylated troponin T (P-Ser(208)-TnT) decreases in LV of HF rats.

Immunological tolerance to muscle autoantigens involves peripheral deletion of autoreactive CD8+ T cells.

Muscle potentially represents the most abundant source of autoantigens of the body and can be targeted by a variety of severe autoimmune diseases. Yet, the mechanisms of immunological tolerance toward muscle autoantigens remain mostly unknown. We investigated this issue in transgenic SM-Ova mice that express an ovalbumin (Ova) neo-autoantigen specifically in skeletal muscle.

Reduction of heart failure by pharmacological inhibition or gene deletion of protein tyrosine phosphatase 1B.

Protein tyrosine phosphatase 1B (PTP1B) regulates tyrosine kinase receptor-mediated responses, and especially negatively influences insulin sensitivity, thus PTP1B inhibitors (PTP1Bi) are currently evaluated in the context of diabetes. We recently revealed another important target for PTP1Bi, consisting in endothelial protection. The present study was designed to test whether reduction of PTP1B activity may be beneficial in chronic heart failure (CHF).

Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis.

Objective: Vascular rejection after organ transplantation is characterized by an arterial occlusive lesion, resulting from intimal proliferation occurring in response to arterial wall immune aggression. Our hypothesis is that an early endothelial repair may prevent vascular graft rejection. The aim of the current study was to compare different pharmacologic progenitor cell mobilizing treatments for their protective effects against vascular rejection.

Heart rate reduction induced by the if current inhibitor ivabradine improves diastolic function and attenuates cardiac tissue hypoxia.

Aims: Enhanced heart rate (HR) is a compensatory mechanism in chronic heart failure (CHF), preserving cardiac output, but at the cost of increased left ventricular (LV) oxygen consumption and impaired diastolic function. The HR reduction (HRR) induced by the If current inhibitor ivabradine prevents LV systolic dysfunction in CHF, but whether HRR improves LV diastolic function is unknown.

Methods: LV diastolic function and remodeling were assessed in rats with CHF after coronary ligation after long-term (90 days, starting 7 days after ligation) and delayed short-term (4 days, starting 93 days after ligation) ivabradine treatment (10 mg·kg·d).

Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure.

Background: Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure.

Methods And Results: First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro.

In vitro and ex vivo evaluation of smart infra-red fluorescent caspase-3 probes for molecular imaging of cardiovascular apoptosis.

Purpose. The aim of this paper is to develop new optical bioprobes for the imaging of apoptosis. Procedure.

Soluble epoxide hydrolase inhibition prevents coronary endothelial dysfunction in mice with renovascular hypertension.

Objectives: The study addresses the hypothesis that endothelial dysfunction in experimental arterial hypertension can be related to an alteration in epoxyeicosatrienoic acids (EETs) pathway and can be prevented by the inhibition of EETs degradation by soluble epoxide hydrolase (sEH).

Methods And Results: Arterial hypertension was induced in FVB/N mice by renal artery stenosis ('two-kidney-one-clip', 2K1C). Seven weeks after surgery, increased aortic pressures (Millar tonometer; Millar Instruments, Houston, Texas, USA) and cardiac hypertrophy (echocardiography) were present in 2K1C mice as compared with control mice.

Protective effect of mycophenolate mofetil on endothelial function in an aortic allograft model.

Background: Whether mycophenolate mofetil (MMF) can prevent the vascular endothelial dysfunction related to the administration of calcineurin inhibitor after organ transplantation remains unknown.

Methods: Four groups of Lewis rats, grafted with Brown Norway donor aortic abdominal allograft, received since the transplantation cyclosporine A (CsA, 5 mg/kg/day), MMF (40 mg/kg/day), CsA+MMF, or vehicle (control) for 2 weeks.

Results: Fifteen days after transplantation, all immunosuppressive regimens were equally effective in preventing graft rejection.

Brain death provokes very acute alteration in myocardial morphology detected by echocardiography: preventive effect of beta-blockers.

Our objective was to evaluate immediate acute changes in myocardial function during the autonomic storm of brain death (BD). Wistar rats were divided into four groups (n = 8/group): controls without any treatment, β-blocker (Esmolol®, 10 mg/kg), calcium channel blocker (Diltiazem®, 10 mg/kg), or alpha-blocker (Prazosin®, 0.3 mg/kg).