Microtubules Sequester Acetylated YAP in the Cytoplasm and Inhibit Heart Regeneration.

Background: The Hippo pathway effector YAP (Yes-associated protein) plays an essential role in cardiomyocyte proliferation and heart regeneration. In response to physiological changes, YAP moves in and out of the nucleus. The pathophysiological mechanisms regulating YAP subcellular localization after myocardial infarction remain poorly defined.

YAP induces a neonatal-like pro-renewal niche in the adult heart.

After myocardial infarction (MI), mammalian hearts do not regenerate, and the microenvironment is disrupted. Hippo signaling loss of function with activation of transcriptional co-factor YAP induces heart renewal and rebuilds the post-MI microenvironment. In this study, we investigated adult renewal-competent mouse hearts expressing an active version of YAP, called YAP5SA, in cardiomyocytes (CMs).

Endothelial cells adopt a pro-reparative immune responsive signature during cardiac injury.

Modulation of the heart's immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have immune regulatory functions; however, interactions between ECs and the immune environment in the heart after MI remain poorly understood. We identified an EC-specific IFN responsive and immune regulatory gene signature in adult and pediatric heart failure (HF) tissues.

ERBB2 drives YAP activation and EMT-like processes during cardiac regeneration.

Cardiomyocyte loss after injury results in adverse remodelling and fibrosis, inevitably leading to heart failure. The ERBB2-Neuregulin and Hippo-YAP signalling pathways are key mediators of heart regeneration, yet the crosstalk between them is unclear. We demonstrate that transient overexpression of activated ERBB2 in cardiomyocytes (OE CMs) promotes cardiac regeneration in a heart failure model.

Synergistic reduction in albuminuria in type 2 diabetic mice by esaxerenone (CS-3150), a novel nonsteroidal selective mineralocorticoid receptor blocker, combined with an angiotensin II receptor blocker.

Esaxerenone is a novel selective mineralocorticoid receptor (MR) blocker that was recently approved in Japan to treat hypertension. In phase II and III studies, esaxerenone plus a renin-angiotensin system inhibitor markedly reduced the urinary albumin-to-creatinine ratio (UACR) in hypertensive patients with diabetic nephropathy. To evaluate a direct renoprotective effect by MR blockade independent of an antihypertensive effect in the context of diabetic nephropathy, esaxerenone (3 mg/kg), olmesartan (an angiotensin II receptor blocker; 1 mg/kg), or both were orally administered to KK-Ay mice, a type 2 diabetes model, once daily for 56 days.

YAP Partially Reprograms Chromatin Accessibility to Directly Induce Adult Cardiogenesis In Vivo.

Specialized adult somatic cells, such as cardiomyocytes (CMs), are highly differentiated with poor renewal capacity, an integral reason underlying organ failure in disease and aging. Among the least renewable cells in the human body, CMs renew approximately 1% annually. Consistent with poor CM turnover, heart failure is the leading cause of death.

maintains mitochondrial function during regeneration to prevent myocardial fat deposition.

Loss of the paired-like homeodomain transcription factor 2 () in cardiomyocytes predisposes mice to atrial fibrillation and compromises neonatal regenerative capacity. In addition, gain-of-function protects mature cardiomyocytes from ischemic injury and promotes heart repair. Here, we characterized the long-term myocardial phenotype following myocardial infarction (MI) in conditional-knockout ( CKO) mice.

Vasodilator-stimulated phosphoprotein (VASP) is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and antiplatelet effect of prasugrel in rats.

Vasodilator-stimulated phosphoprotein (VASP) is a member of actin regulatory proteins implicated in platelet adhesion. In addition, phosphorylation of VASP is utilised for the assessment of platelet reactivity in patients treated with P2Y receptor antagonists, a class of antiplatelet agents. However, the role of VASP in platelet aggregation, thrombogenesis, haemostasis, and the antiplatelet effect of P2Y receptor antagonists remains unclear.

Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development.

During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts.

Hippo pathway deficiency reverses systolic heart failure after infarction.

Mammalian organs vary widely in regenerative capacity. Poorly regenerative organs, such as the heart are particularly vulnerable to organ failure. Once established, heart failure commonly results in mortality.

Dystrophin-glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation.

The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis. Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy. The Hippo pathway, a conserved kinase cascade, inhibits cardiomyocyte proliferation in the developing heart to control heart size and prevents regeneration in the adult heart.

CS-3150, a Novel Nonsteroidal Mineralocorticoid Receptor Antagonist, Shows Preventive and Therapeutic Effects On Renal Injury in Deoxycorticosterone Acetate/Salt-Induced Hypertensive Rats.

The present study was designed to assess both preventive and therapeutic effects of (S)-1-(2-Hydroxyethyl)-4-methyl-N-[4-(methylsulfonyl) phenyl]-5-[2-(trifluoromethyl) phenyl]-1H-pyrrole-3-carboxamide (CS-3150), a novel nonsteroidal mineralocorticoid receptor antagonist, on renal injury in deoxycorticosterone acetate (DOCA)/salt-induced hypertensive rats (DOCA rats). From 7 weeks of age, DOCA was subcutaneously administered once a week for 4 weeks to uninephrectomized rats fed a high-salt diet. In experiment 1, CS-3150 (0.

Pitx2 promotes heart repair by activating the antioxidant response after cardiac injury.

Myocardial infarction results in compromised myocardial function and heart failure owing to insufficient cardiomyocyte self-renewal. Unlike many vertebrates, mammalian hearts have only a transient neonatal renewal capacity. Reactivating primitive reparative ability in the mature mammalian heart requires knowledge of the mechanisms that promote early heart repair.

Pharmacological profile of CS-3150, a novel, highly potent and selective non-steroidal mineralocorticoid receptor antagonist.

The present study was designed to characterize the pharmacological profile of CS-3150, a novel non-steroidal mineralocorticoid receptor antagonist. In the radioligand-binding assay, CS-3150 inhibited (3)H-aldosterone binding to mineralocorticoid receptor with an IC50 value of 9.4nM, and its potency was superior to that of spironolactone and eplerenone, whose IC50s were 36 and 713nM, respectively.

Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice.

The mammalian heart regenerates poorly, and damage commonly leads to heart failure. Hippo signaling is an evolutionarily conserved kinase cascade that regulates organ size during development and prevents adult mammalian cardiomyocyte regeneration by inhibiting the transcriptional coactivator Yap, which also responds to mechanical signaling in cultured cells to promote cell proliferation. To identify Yap target genes that are activated during cardiomyocyte renewal and regeneration, we performed Yap chromatin immunoprecipitation sequencing (ChIP-Seq) and mRNA expression profiling in Hippo signaling-deficient mouse hearts.

Predicting goals in action episodes attenuates BOLD response in inferior frontal and occipitotemporal cortex.

Actions are usually made of several action steps gearing towards an overarching goal. During observation of such action episodes the overarching action goal becomes more and more clear and upcoming action steps can be predicted with increasing precision. To tap this process, the present fMRI study investigated the dynamic changes of neural activity during the observation of distinct action steps that cohere by an overarching goal.

Noncontact quantitative biomechanical characterization of cardiac muscle using shear wave imaging optical coherence tomography.

We report on a quantitative optical elastographic method based on shear wave imaging optical coherence tomography (SWI-OCT) for biomechanical characterization of cardiac muscle through noncontact elasticity measurement. The SWI-OCT system employs a focused air-puff device for localized loading of the cardiac muscle and utilizes phase-sensitive OCT to monitor the induced tissue deformation. Phase information from the optical interferometry is used to reconstruct 2-D depth-resolved shear wave propagation inside the muscle tissue.

Hippo signaling impedes adult heart regeneration.

Heart failure due to cardiomyocyte loss after ischemic heart disease is the leading cause of death in the United States in large part because heart muscle regenerates poorly. The endogenous mechanisms preventing mammalian cardiomyocyte regeneration are poorly understood. Hippo signaling, an ancient organ size control pathway, is a kinase cascade that inhibits developing cardiomyocyte proliferation but it has not been studied postnatally or in fully mature adult cardiomyocytes.

Nfat and miR-25 cooperate to reactivate the transcription factor Hand2 in heart failure.

Although aberrant reactivation of embryonic gene programs is intricately linked to pathological heart disease, the transcription factors driving these gene programs remain ill-defined. Here we report that increased calcineurin/Nfat signalling and decreased miR-25 expression integrate to re-express the basic helix-loop-helix (bHLH) transcription factor dHAND (also known as Hand2) in the diseased human and mouse myocardium. In line, mutant mice overexpressing Hand2 in otherwise healthy heart muscle cells developed a phenotype of pathological hypertrophy.

Bmp signaling represses Vegfa to promote outflow tract cushion development.

Congenital heart disease (CHD) is a devastating anomaly that affects ∼1% of live births. Defects of the outflow tract (OFT) make up a large percentage of human CHD. We investigated Bmp signaling in mouse OFT development by conditionally deleting both Bmp4 and Bmp7 in the second heart field (SHF).

Expression level of Hand2 affects specification of enteric neurons and gastrointestinal function in mice.

Background & Aims: Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival, but not for development of a normal enteric nervous system (ENS).

Methods: Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified.

Transbronchial occlusion of a malignant bronchopleural fistula with cyanoacrylate glue.

A 73-year-old man who had undergone surgery for lingual cancer, followed by radiation therapy and chemotherapy, presented with severe dyspnea. A chest radiograph revealed a left tension pneumothorax. An immediate tube thoracostomy alleviated his dyspnea.