Insulin and Insulin-Like Growth Factor 1 Signaling Preserves Sarcomere Integrity in the Adult Heart.

Insulin and insulin-like growth factor 1 (IGF1) signaling is transduced by insulin receptor substrate 1 (IRS1) and IRS2. To elucidate physiological and redundant roles of insulin and IGF1 signaling in adult hearts, we generated mice with inducible cardiomyocyte-specific deletion of insulin and IGF1 receptors or IRS1 and IRS2. Both models developed dilated cardiomyopathy, and most mice died by 8 weeks post-gene deletion.

Altered compositions of monocyte, T lymphocyte and NK cell subsets in heart failure of adult congenital heart disease.

Background: Adults with congenital heart disease (ACHD) display changes in adaptive immunity related to early open-heart surgery and subsequent incidental thymectomy. In acquired heart failure (HF) systemic inflammation, innate and adaptive immune cells play an important role. However, cellular immune alterations of monocyte, T lymphocyte and natural killer (NK) cell subsets have not been related to HF in ACHD.

Expansion of CD10 neutrophils and CD14HLA-DR monocytes driving proinflammatory responses in patients with acute myocardial infarction.

Immature neutrophils and HLA-DR monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored. We found an expansion of circulating immature CD16CD66bCD10 neutrophils and CD14HLA-DR monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10 neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis.

Genetic ablation of fibroblast activation protein alpha attenuates left ventricular dilation after myocardial infarction.

Introduction: Regulating excessive activation of fibroblasts may be a promising target to optimize extracellular matrix deposition and myocardial stiffness. Fibroblast activation protein alpha (FAP) is upregulated in activated fibroblasts after myocardial infarction (MI), and alters fibroblast migration in vitro. We hypothesized that FAP depletion may have a protective effect on left ventricular (LV) remodeling after MI.

Macrophage Mineralocorticoid Receptor Is a Pleiotropic Modulator of Myocardial Infarct Healing.

Myocardial infarction (MI) is a major cause of death worldwide. Here, we identify the macrophage MR (mineralocorticoid receptor) as a crucial pathogenic player in cardiac wound repair after MI. Seven days after left coronary artery ligation, mice with myeloid cell-restricted MR deficiency compared with WT (wild type) controls displayed improved cardiac function and remodeling associated with enhanced infarct neovascularization and scar maturation.

Modeling Cardiac Fibrosis in Mice: (Myo)Fibroblast Phenotype After Ischemia.

Cardiac (myo)fibroblasts play a key role in the regulation of wound healing and pathogenic remodeling after myocardial infarction. Impaired scar formation and alterations of the extracellular matrix network precipitate cardiac dysfunction leading to increased morbidity and mortality. Therapeutic approaches addressing (myo)fibroblast phenotype appear to be useful in preventing progressive structural, electrical, and functional impairment and heart failure.

Intermediate CD14++CD16+ monocytes decline after transcatheter aortic valve replacement and correlate with functional capacity and left ventricular systolic function.

Background: Transcatheter aortic valve replacement (TAVR) is the method of choice for patients with severe aortic valve stenosis, who are ineligible or at high risk for surgery. Though TAVR leads to a significant reduction in mortality, a notable amount of patients are re-hospitalized early after TAVR. Parameters or biomarkers predicting outcome are therefore needed to identify patients who benefit most.

The glucocorticoid receptor in monocyte-derived macrophages is critical for cardiac infarct repair and remodeling.

Cell- and tissue-specific actions of glucocorticoids are mediated by the glucocorticoid receptor. Here, we demonstrate that the glucocorticoid receptor (GR) in macrophages is essential for cardiac healing after myocardial infarction. Compared with GR (wild-type controls), GR mice that lacked GR in myeloid cells showed increased acute mortality as a result of cardiac rupture.

Changes in concentrations of circulating fibroblast activation protein alpha are associated with myocardial damage in patients with acute ST-elevation MI.

Background: Fibroblast activation protein alpha (FAP) is a membrane-bound serine protease expressed by activated fibroblasts after myocardial infarction (MI). Reduced circulating FAP levels were associated with increased mortality in patients with acute coronary syndrome. We hypothesized that FAP concentrations are altered after acute ST-elevation MI (STEMI), and related to myocardial damage.

Pentaerythritol Tetranitrate Targeting Myocardial Reactive Oxygen Species Production Improves Left Ventricular Remodeling and Function in Rats With Ischemic Heart Failure.

Reduced nitric oxide bioavailability contributes to progression of cardiac dysfunction and remodeling in ischemic heart failure. Clinical use of organic nitrates as nitric oxide donors is limited by development of nitrate tolerance and reactive oxygen species formation. We investigated the effects of long-term therapy with pentaerythritol tetranitrate (PETN), an organic nitrate devoid of tolerance, in rats with congestive heart failure after extensive myocardial infarction.

Efficacy of mineralocorticoid receptor antagonism in the acute myocardial infarction phase: eplerenone versus spironolactone.

Aims: The selective mineralocorticoid receptor (MR) antagonist eplerenone given early in patients with acute myocardial infarction (MI) improves clinical outcome, whereas little is known about the effectiveness of early spironolactone therapy. We aimed to compare the ability of eplerenone and spironolactone to promote cardiac repair after experimental MI.

Methods And Results: Starting immediately after coronary artery ligation, C57BL/6J mice were treated with placebo, eplerenone, or spironolactone.

Fibroblast activation protein alpha expression identifies activated fibroblasts after myocardial infarction.

Introduction: Fibroblast activation protein α (FAP) is a membrane-bound serine protease expressed by activated fibroblasts during wound healing in the skin. Expression of FAP after myocardial infarction (MI) and potential effects on cardiac wound healing are largely unknown.

Methods: MI was induced in rats and FAP expression was analyzed at 3, 7 and 28 days post-MI by microarray, Western blot and immunohistochemistry.

Soluble guanylyl cyclase activation improves progressive cardiac remodeling and failure after myocardial infarction. Cardioprotection over ACE inhibition.

Impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cGMP signaling is involved in the pathogenesis of ischemic heart diseases, yet the impact of long-term sGC activation on progressive cardiac remodeling and heart failure after myocardial infarction (MI) has not been explored. Moreover, it is unknown whether stimulating the NO/heme-independent sGC provides additional benefits to ACE inhibition in chronic ischemic heart failure. Starting 10 days after MI, rats were treated with placebo, the sGC activator ataciguat (10 mg/kg/twice daily), ramipril (1 mg/kg/day), or a combination of both for 9 weeks.

Circulating concentrations of fibroblast activation protein α in apparently healthy individuals and patients with acute coronary syndrome as assessed by sandwich ELISA.

Background: Fibroblast activation protein α (FAP) is a membrane glycoprotein with dipeptidyl-peptidase and collagenase activity and is expressed in cancer, arthritis, and atherosclerotic plaques. We hypothesized that FAP can be measured quantitatively in the circulation and provide prognostic information in acute coronary syndrome (ACS).

Methods: We assessed the performance of a commercially available FAP ELISA and the pre-analytic characteristics of the marker.

MicroRNA-22 increases senescence and activates cardiac fibroblasts in the aging heart.

MicroRNAs (miRs) are small non- coding RNA molecules controlling a plethora of biological processes such as development, cellular survival and senescence. We here determined miRs differentially regulated during cardiac postnatal development and aging. Cardiac function, morphology and miR expression profiles were determined in neonatal, 4 weeks, 6 months and 19 months old normotensive male healthy C57/Bl6N mice.

Mineralocorticoid receptor activation in myocardial infarction and failure: recent advances.

The classical view of aldosterone actions via the mineralocorticoid receptor (MR) limited to control of fluid balance and blood pressure homoeostasis has been progressively overcome by clinical and experimental evidence emphasizing the pleiotropic role of MR activation in the pathogenesis of cardiovascular disease. Clinical studies have shown the benefit of MR blockade in patients with left ventricular dysfunction and heart failure after myocardial infarction (MI), hypertension or diabetic nephropathy. Deleterious effects of MR activation include cardiac structural and electrical remodelling, cardiovascular fibrosis, inflammation and oxidative stress.

Novel therapeutic approaches to post-infarction remodelling.

Adverse cardiac remodelling is a major cause of morbidity and mortality following acute myocardial infarction (MI). Mechanical and neurohumoral factors involved in structural and molecular post-infarction remodelling were important targets in research and treatment for years. More recently, therapeutic strategies that address myocardial regeneration and pathophysiological mechanisms of infarct wound healing appear to be useful novel tools to prevent progressive ventricular dilation, functional deterioration, life-threatening arrhythmia, and heart failure.

MicroRNA-24 regulates vascularity after myocardial infarction.

Background: Myocardial infarction leads to cardiac remodeling and development of heart failure. Insufficient myocardial capillary density after myocardial infarction has been identified as a critical event in this process, although the underlying mechanisms of cardiac angiogenesis are mechanistically not well understood.

Methods And Results: Here, we show that the small noncoding RNA microRNA-24 (miR-24) is enriched in cardiac endothelial cells and considerably upregulated after cardiac ischemia.

Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction.

Background: Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter.

Methods And Results: Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation.

Increased cytochrome P4502E1 expression and altered hydroxyeicosatetraenoic acid formation mediate diabetic vascular dysfunction: rescue by guanylyl-cyclase activation.

Objective: We investigated the mechanisms underlying vascular endothelial and contractile dysfunction in diabetes as well as the effect of HMR1766, a novel nitric oxide (NO)-independent activator of soluble guanylyl cyclase (sGC).

Research Design And Methods: Two weeks after induction of diabetes by streptozotocin, Wistar rats received either placebo or HMR1766 (10 mg/kg twice daily) for another 2 weeks; thereafter, vascular function was assessed.

Results: Endothelial function and contractile responses were significantly impaired, while vascular superoxide formation was increased in the aortae from diabetic versus healthy control rats.

Short communication: asymmetric dimethylarginine impairs angiogenic progenitor cell function in patients with coronary artery disease through a microRNA-21-dependent mechanism.

Rationale: The endogenous nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA) is increased in patients with coronary artery disease and may regulate function of circulating angiogenic progenitor cells (APCs) by small regulatory RNAs.

Objectives: To study the role of microRNAs in ADMA-mediated impairment of APCs.

Methods And Results: By using microarray analyses, we established microRNA expression profiles of human APCs.

Attenuation of angiotensin II-induced vascular dysfunction and hypertension by overexpression of Thioredoxin 2.

Reactive oxygen species increase in the cardiovascular system during hypertension and in response to angiotensin II. Because mitochondria contribute to reactive oxygen species generation, we sought to investigate the role of thioredoxin 2, a mitochondria-specific antioxidant enzyme. Mice were created with overexpression of human thioredoxin 2 (Tg(hTrx2) mice) and backcrossed to C57BL/6J mice for > or =6 generations.