Signaling In Cardiovascular Disease Research Articles

A Mendelian randomization study of IL6 signaling in cardiovascular diseases, immune-related disorders and longevity

Growing evidence suggests that inflammation is a significant contributor to different cardiovascular diseases (CVDs). Mendelian randomization (MR) was performed to assess the causal inference between plasma soluble IL6 receptor (sIL6R), a negative regulator of IL6 signaling, and different cardiovascular and immune-related disorders. Cis-MR with multiple instrumental variables showed an inverse association of sIL6R with rheumatoid arthritis, atrial fibrillation, stroke, coronary artery disease, and abdominal aortic aneurysm. However, genetically-determined sIL6R level was positively associated with atopic dermatitis and asthma. Also, sIL6R level was associated with longevity, as evaluated by parental age at death, a heritable trait. Gene-based association analysis with S-PrediXcan by using tissues from GTExV7 showed that IL6R tissue expression-disease pair associations were consistent with the directional effect of IL6 signaling identified in MR. Genetically-determined reduced IL6 signaling lowers the risk of multiple CVDs and is associated with increased longevity, but at the expense of higher atopic risk.

Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine.

The Hedgehog (HH) signaling pathway plays an important role in embryonic and postnatal vascular development and in maintaining the homeostasis of organs. Under physiological conditions, Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, regulates endothelial cell growth, promotes cell migration and stimulates the formation of new blood vessels. The present review highlights recent advances made in the field of SHH signaling in endothelial progenitor cells (EPCs). The canonical and non-canonical SHH signaling pathways in EPCs and endothelial cells (ECs) related to homeostasis, SHH signal transmission by extracellular vesicles (EVs) or exosomes containing single-strand non-coding miRNAs and impaired SHH signaling in cardiovascular diseases are discussed. As a promising therapeutic tool, the possibility of using the SHH signaling pathway for the activation of EPCs in patients suffering from cardiovascular diseases is further explored.

The emerging role of aldosterone/mineralocorticoid receptors in the pathogenesis of erectile dysfunction.

Aldosterone is an old hormone that has been discovered for more than fifty years. The clinical application of its receptors' inhibitors, especially spirolactone, has benifited patients for decades worldwide. In this review, we briefly summarized the molecular mechanism of aldosterone/mineralocorticoid receptors (Ald-MRs) signaling in cardiovascular diseases and its emerging role in erectile dysfunction. We searched PubMed, Web of Science, and Scopus for manuscripts published prior to December 2017 using key words " aldosterone " AND " erectile dysfunction " OR " cardiovascular disease " OR " mineralocorticoid receptors ". Related literature and clinical perspectives were collated, summarized and discussed in this review. The increase of reactive oxygen species production, inhibition of endothelial nitric oxide synthase system, and induction of inflammation are ubiquitous in vascular endothelial cells or vascular smooth muscle cells after the activation of Ald-MRs pathway. In addition, in cardiovascular diseases with over-active Ald-MRs signaling, MRs blockade could reverse the injury and improve the prognosis. Notably, multiple studies have correlated aldosterone and MRs to the pathogenesis of erectile function, while the mechanism is largely unperfectly identified. In conclusion, we summarize the current evidence to highlight the potential role of aldosterone in erectile dysfunction and provide critical insights into the treatment of the disease.

How Hippo Signaling Pathway Modulates Cardiovascular Development and Diseases.

Cardiovascular disease remains the leading cause of death around the globe. Cardiac deterioration is associated with irreversible cardiomyocyte loss. Understanding how the cardiovascular system develops and the pathological processes of cardiac disease will contribute to finding novel and preventive therapeutic methods. The canonical Hippo tumor suppressor pathway in mammalian cells is primarily composed of the MST1/2-SAV1-LATS1/2-MOB1-YAP/TAZ cascade. Continuing research on this pathway has identified other factors like RASSF1A, Nf2, MAP4Ks, and NDR1/2, further enriching our knowledge of the Hippo-YAP pathway. YAP, the core effecter of the Hippo pathway, may accumulate in the nucleus and initiate transcriptional activity if the pathway is inhibited. The role of Hippo signaling has been widely investigated in organ development and cancers. A heart of normal size and function which is critical for survival could not be generated without the proper regulation of the Hippo tumor suppressor pathway. Recent research has demonstrated a novel role of Hippo signaling in cardiovascular disease in the context of development, hypertrophy, angiogenesis, regeneration, apoptosis, and autophagy. In this review, we summarize the current knowledge of how Hippo signaling modulates pathological processes in cardiovascular disease and discuss potential molecular therapeutic targets.

Wnt signaling in cardiovascular disease: opportunities and challenges.

Cardiometabolic diseases increasingly afflict our aging, dysmetabolic population. Complex signals regulating low-density lipoprotein receptor-related protein (LRP) and frizzled protein family members - the plasma membrane receptors for the cadre of Wnt polypeptide morphogens - contribute to the control of cardiovascular homeostasis. Both canonical (β-catenin-dependent) and noncanonical (β-catenin-independent) Wnt signaling programs control vascular smooth muscle (VSM) cell phenotypic modulation in cardiometabolic disease. LRP6 limits VSM proliferation, reduces arteriosclerotic transcriptional reprogramming, and preserves insulin sensitivity while LRP5 restrains foam cell formation. Adipose, skeletal muscle, macrophages, and VSM have emerged as important sources of circulating Wnt ligands that are dynamically regulated during the prediabetes-diabetes transition with cardiometabolic consequences. Platelets release Dkk1, a LRP5/LRP6 inhibitor that induces endothelial inflammation and the prosclerotic endothelial-mesenchymal transition. By contrast, inhibitory secreted frizzled-related proteins shape the Wnt signaling milieu to limit myocardial inflammation with ischemia-reperfusion injury. VSM sclerostin, an inhibitor of canonical Wnt signaling in bone, restrains remodeling that predisposes to aneurysm formation, and is downregulated in aneurysmal vessels by epigenetic methylation. Components of the Wnt signaling cascade represent novel targets for pharmacological intervention in cardiometabolic disease. Conversely, strategies targeting the Wnt signaling cascade for other therapeutic purposes will have cardiovascular consequences that must be delineated to establish clinically useful pharmacokinetic-pharmacodynamic relationships.

Dysregulation of GPCR Signaling in Cardiovascular Diseases: A Potential Role for Exercise Training?

PURPOSE: The superfamily of G protein-coupled receptors (GPCR) are activated by biological molecules (e.g. neurotransmitters) and are involved in many physiological events. As exaggerated GPCR-mediated signaling may contribute to cardiovascular disorders, RGS proteins (regulators of G-protein signaling) are viewed as an important regulatory molecule for the negative modulation of this signaling pathway. To address the significance of RGS proteins and suggest potential effects of exercise training on this molecule, a literature review on RGS proteins was conducted. METHODS: A systemic search in PUBMED was performed to obtain previous studies investigating roles of RGS proteins in the cardio-vascular systems. RESULTS: RGS proteins directly bind to the Gα subunit of heterotrimeric G proteins to inhibit GPCR signaling pathways and terminate their activity. Using mice genetically lacking RGS2 and RGS5, these proteins have been shown to contribute to pressure overloadinduced cardiac remodeling. Further, it has been suggested that systemic knockout of RGS2 protein causes hypertension by potentiating G protein signaling-mediated vascular responses and impairing nitric oxide/cGMP-induced vasorelaxation. Thus, RGS proteins have been suggested as potential drug targets for cardiovascular disorders accompanied by dysregulation of RGS proteins and GPCR signaling. Although exercise training has also been well-documented to strengthen cardiovascular function and ameliorate circulatory diseases, cellular mechanisms underlying the contribution of exercise intervention to RGS-mediated GPCR signaling have not been explored. CONCLUSIONS: This brief review discusses roles played by RGS proteins in the cardiovascular system and suggests future studies for investigating the interaction between exercise training and RGS protein-mediated regulation of GPCR signaling.

PI3K and Calcium Signaling in Cardiovascular Disease.

Receptor signaling relays on intracellular events amplified by secondary and tertiary messenger molecules. In cardiomyocytes and smooth muscle cells, cyclic AMP (cAMP) and subsequent calcium (Ca2+) fluxes are the best characterized receptor-regulated signaling events. However, most of receptors able to modify contractility and other intracellular responses signal through a variety of other messengers, and whether these signaling events are interconnected has long remained unclear. For example, the PI3K (phosphoinositide 3-kinase) pathway connected to the production of the lipid second messenger PIP3/PtdIns(3,4,5)P3 (phosphatidylinositol (3,4,5)-trisphosphate) is potentially involved in metabolic regulation, activation of hypertrophy, and survival pathways. Recent studies, highlighted in this review, started to interconnect PI3K pathway activation to Ca2+ signaling. This interdependency, by balancing contractility with metabolic control, is crucial for cells of the cardiovascular system and is emerging to play key roles in disease development. Better understanding of the interplay between Ca2+ and PI3K signaling is, thus, expected to provide new ground for therapeutic intervention. This review explores the emerging molecular mechanisms linking Ca2+ and PI3K signaling in health and disease.

TGF-β Signaling in Control of Cardiovascular Function.

Genetic studies in animals and humans indicate that gene mutations that functionally perturb transforming growth factor β (TGF-β) signaling are linked to specific hereditary vascular syndromes, including Osler-Rendu-Weber disease or hereditary hemorrhagic telangiectasia and Marfan syndrome. Disturbed TGF-β signaling can also cause nonhereditary disorders like atherosclerosis and cardiac fibrosis. Accordingly, cell culture studies using endothelial cells or smooth muscle cells (SMCs), cultured alone or together in two- or three-dimensional cell culture assays, on plastic or embedded in matrix, have shown that TGF-β has a pivotal effect on endothelial and SMC proliferation, differentiation, migration, tube formation, and sprouting. Moreover, TGF-β can stimulate endothelial-to-mesenchymal transition, a process shown to be of key importance in heart valve cushion formation and in various pathological vascular processes. Here, we discuss the roles of TGF-β in vasculogenesis, angiogenesis, and lymphangiogenesis and the deregulation of TGF-β signaling in cardiovascular diseases.

The Role of Nrf2 in Cardiovascular Function and Disease.

Free radicals, reactive oxygen/nitrogen species (ROS/RNS), hydrogen sulphide, and hydrogen peroxide play an important role in both intracellular and intercellular signaling; however, their production and quenching need to be closely regulated to prevent cellular damage. An imbalance, due to exogenous sources of free radicals and chronic upregulation of endogenous production, contributes to many pathological conditions including cardiovascular disease and also more general processes involved in aging. Nuclear factor erythroid 2-like 2 (NFE2L2; commonly known as Nrf2) is a transcription factor that plays a major role in the dynamic regulation of a network of antioxidant and cytoprotective genes, through binding to and activating expression of promoters containing the antioxidant response element (ARE). Nrf2 activity is regulated by many mechanisms, suggesting that tight control is necessary for normal cell function and both hypoactivation and hyperactivation of Nrf2 are indicated in playing a role in different aspects of cardiovascular disease. Targeted activation of Nrf2 or downstream genes may prove to be a useful avenue in developing therapeutics to reduce the impact of cardiovascular disease. We will review the current status of Nrf2 and related signaling in cardiovascular disease and its relevance to current and potential treatment strategies.

Roles and regulation of protein phosphatase 2A (PP2A) in the heart

Reversible protein phosphorylation is central to a variety of cardiac processes including excitation-contraction coupling, Ca2+ handling, cell metabolism, myofilament regulation, and cell-cell communication. While kinase pathways linked with elevated adrenergic signaling have been a major focus for the cardiovascular field over the past half century, new findings support the critical role of protein phosphatases in both health and disease. Protein phosphatase 2A (PP2A) is a central cardiac phosphatase that regulates diverse myocyte functions through a host of target molecules. Notably, multiple mechanisms have evolved to dynamically tune PP2A function, including modulation of the composition, phosphorylation, methylation, and localization of PP2A holoenzyme populations. Further, aberrations in this regulation of PP2A function may contribute to cardiac pathophysiology. In summary, PP2A is a critical regulatory molecule in both health and disease, with a myriad of targets in heart. Based on their unique structure, localization, and regulatory properties, PP2A subunits represent exciting therapeutic targets to modulate altered adrenergic signaling in cardiovascular disease.

Abstract 353: P2Y 2 Nucleotide Receptor Overexpression: Letting Blind Cardiac Progenitor Cells ‘See’ Again

Heart failure (HF) is a leading cause of death in the US due to limited capability of adult mammalian heart to regenerate after myocardial infarction (MI). Autologous stem cell therapy holds promise for promoting regeneration of injured heart but stem cells derived from diseased organs exhibit poor proliferative, migratory and survival capabilities. Empowering cardiac-derived progenitor cells (CPC) with prosurvival genes has been attempted. However, molecular mechanisms by which stem cells detect stress signals to subsequently initiate appropriate regenerative responses are poorly understood. In this regard, purinergic receptors represent a major detector for extracellular nucleotides released during injury/stress and serve as an intracellular platform harboring numerous signaling pathways that regulate proinflammatory and regenerative responses required for the healing process. Despite the established roles of purinergic signaling in cardiovascular diseases, it has not been well-defined in CPCs. This study shows, for the first time, that the majority of P2 purinergic receptors are expressed and exhibit functional responses to ATP and UTP in human CPCs (hCPC) isolated from HF patients. The G protein-coupled P2Y 2 R is a pivotal stress detector that senses ATP and UTP accumulated in extracellular space after injury and mediates regenerative responses in various injury models, including MI model, and in stem cells from diverse origins. Interestingly, hCPCs with relatively slower growth kinetics and enhanced senescence show dramatic decreases in P2Y 2 receptor (P2Y 2 R) expression compared to fast-growing hCPCs, consistent with our hypothesis that overexpressing P2Y 2 R enables diseased hCPCs to better detect stress stimuli and react with the proper regenerative responses. Along this line, P2Y 2 R stimulation with UTP enhances hCPC proliferation and migration. Interestingly, preliminary results demonstrate that UTP treatment induces YAP activation and nuclear shuttling. Moreover, inhibition of YAP/TEAD interaction impairs UTP-induced proliferation and migration revealing a novel link between extracellular nucleotides released during cardiac ischemia and Hippo signaling that has been recently implicated in cardiac regeneration.

P-165: Protective role of nucleotidases against the development of hypertension

Background Hypertension is associated with a hypertrophic remodeling of big arteries, oxidative stress and inflammation. Extracellular nucleotides, released under stress condition, play a role in various physiopathological conditions through P2 receptors activation. Hydrolysis of nucleotides is achieved by nucleoside triphosphate diphosphohydrolases, in particular NTPDase1 (CD39) which is highly expressed in the arterial wall. Together with ecto-5’nucleotidase (CD73), these ectoenzymes generate vasoprotective adenosine. The contribution of the purinergic signaling in cardiovascular diseases, hypertension in particular, remains to be established. Here, we investigate the potential benefit of extracellular nucleotidase in experimental hypertension by treating hypertensive mice with the potato ATPDase, Apyrase. Methods Experimental hypertension was induced by Angiotensin II (AngII, subcutaneous 1mg/kg/day, osmotic pumps). Endogenous CD39 arterial expression and serum activity of hypertensive mice was evaluated by quantitative RT-PCR and by HPLC respectively (incubated with fluorescent etheno-ADP as a substrate). To replete mice with exogenous nucleotidase activity mice were treated or not with Apyrase (APY 90U/kg/day and 500U/kg ip every 3 days). Blood pressure was recorded daily by tail cuff plethys-mography until day 12 the day of the sacrifice. Then, media thickness of thoracic aorta was measured by histomorphometry, oxidative stress was evaluated with dihydroethidium staining and Immune cells infiltration was assessed by Immunofluorescence using pan immune cells marker (CD45) or macrophages marker (F4/80). Data were corroborated by quantitative RT-PCR. Results We found a decrease in both CD39 arterial expression and serum activity in AngII-treated mice, suggesting a link of the endogenous ectonucleotidase CD39 to hypertension. In accordance with a protective role of nucleotidase activity, blood pressure increase and hypertrophic arterial remodeling were significantly reduced in AngII/APY-treated mice compared to AngII alone. Moreover, RT-qPCR and immunofluorescence experiments evidenced decreased perivascular immune cells infiltration and oxidative stress in AngII/APY-treated mice compared to AngII-treated mice. Conclusions Nucleotidase activities protect against vascular alterations associated to hypertension while the expression of CD39 decreases with the pathology. Nucleotidase may represent new therapeutic treatment for vascular diseases.

Regulation of CaMKII signaling in cardiovascular disease.

Heart failure (HF) is a major cause of death in the developed countries (Murray and Lopez, 1996; Koitabashi and Kass, 2012). Adverse cardiac remodeling that precedes heart muscle dysfunction is characterized by a myriad of molecular changes affecting the cardiomyocyte. Among these, alterations in protein kinase pathways play often an important mediator role since they link upstream pathologic stress signaling with downstream regulatory programs and thus affect both the structural and functional integrity of the heart muscle. In the context of cardiac disease, a profound understanding for the overriding mechanisms that regulate protein kinase activity (protein-protein interactions, post-translational modifications, or targeting via anchoring proteins) is crucial for the development of specific and effective pharmacological treatment strategies targeting the failing myocardium. In this review, we focus on several mechanisms of upstream regulation of Ca2+-calmodulin-dependent protein kinase II that play a relevant pathophysiological role in the development and progression of cardiovascular disease; precise targeting of these mechanisms might therefore represent novel and promising tools for prevention and treatment of HF.

The activated endocannabinoid system in atherosclerosis: driving force or protective mechanism?

Atherosclerosis and its major acute complications, myocardial infarction and stroke, are the leading causes of death and morbidity worldwide. Despite major advances in cardiovascular intervention and healthcare, improving preventive care and treatment remains a continuous mission for cardiovascular research. Within the last 10 to 15 years, the endocannabinoid system has emerged as an important lipid signaling system involved in many biological processes. Growing evidence suggests that an overactive endocannabinoid-CB1 receptor signaling promotes the development of cardiovascular risk factors such as obesity, insulin resistance and dyslipidemia. This prompted an increasing interest in studying the role of the endocannabinoid system in atherosclerosis. As opposed to the detrimental actions of CB1 signaling, the endocannabinoid-CB2 receptor axis exhibits an anti-inflammatory and atheroprotective role. We will review recent findings from experimental and clinical studies aimed at understanding the complex actions of endocannabinoid signaling in cardiovascular disease. This is followed by an outlook on emerging targets for possible therapeutic intervention.

Mitogen-activated protein kinase phosphatase-1: a critical phosphatase manipulating mitogen-activated protein kinase signaling in cardiovascular disease (review).

Mitogen-activated protein kinase (MAPK) cascades are important players in the overall representation of cellular signal transduction pathways, and the deregulation of MAPKs is involved in a variety of diseases. The activation of MAPK signals occurs through phosphorylation by MAPK kinases at conserved threonine and tyrosine (Thr-Xaa-Tyr) residues. The mitogen-activated protein kinase phosphatases (MKPs) are a major part of the dual-specificity family of phosphatases and specifically inactivate MAPKs by dephosphorylating both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. MAPKs binding to MKPs can enhance MKP stability and activity, providing an important negative-feedback control mechanism that limits the MAPK cascades. In recent years, accumulating and compelling evidence from studies mainly employing cultured cells and mouse models has suggested that the archetypal MKP family member, MKP-1, plays a pivotal role in cardiovascular disease as a major negative modulator of MAPK signaling pathways. In the present review, we summarize the current knowledge on the pathological properties and the regulation of MKP-1 in cardiovascular disease, which may provide valuable therapeutic options.

Targeting Wnt-Frizzled signaling in cardiovascular diseases

Wnts are secreted glycoproteins implicated in biological processes ranging from embryonic cardiac development to uncontrolled cell proliferation in diseased conditions. Cardiovascular disease is a major cause of morbidity and mortality worldwide. Phenotypic modulation of vascular smooth muscle cells, migration and proliferation in intimal layer and increased extracellular matrix production are some of the known hallmarks of cardiovascular pathologies. Heterogeneity associated with the binding of Wnts to their transmembrane receptors, Frizzled, and coreceptors low density lipoprotein-receptor-related protein is indeed intriguing. Nuclear-cytoplasmic shuttling of beta-catenin and activation of transcriptional factors, lymphoid enhancer factor and T cell activation factor leading to target gene activation has remained elusive. Our review highlights the emerging role of Wnt-Frizzled signaling in cardiovascular diseases. Overall, the pathway appears to be an attractive therapeutic target in identifying susceptible individuals at risk of developing restenosis/other vascular pathologies in the near future.

Therapeutic Potential of Pde Modulation in Treating Heart Disease

Altered cyclic nucleotide-mediated signaling plays a critical role in the development of cardiovascular pathology. By degrading cAMP/cGMP, the action of cyclic nucleotide PDEs is essential for controlling cyclic nucleotide-mediated signaling intensity, duration, and specificity. Altered expression, localization and action of PDEs have all been implicated in causing changes in cyclic nucleotide signaling in cardiovascular disease. Accordingly, pharmacological inhibition of PDEs has gained interest as a treatment strategy and as an area of drug development. While targeting of certain PDEs has the potential to ameliorate cardiovascular disease, inhibition of others might actually worsen it. This review will highlight recent research on the physiopathological role of cyclic nucleotide signaling, especially with regard to PDEs. While the physiological roles and biochemical properties of cardiovascular PDEs will be summarized, the primary emphasis will be pathological. Research into the potential benefits and hazards of PDE inhibition will also be discussed.

Impact of exercise training on redox signaling in cardiovascular diseases

Reactive oxygen and nitrogen species regulate a wide array of signaling pathways that governs cardiovascular physiology. However, oxidant stress resulting from disrupted redox signaling has an adverse impact on the pathogenesis and progression of cardiovascular diseases. In this review, we address how redox signaling and oxidant stress affect the pathophysiology of cardiovascular diseases such as ischemia-reperfusion injury, hypertension and heart failure. We also summarize the benefits of exercise training in tackling the hyperactivation of cellular oxidases and mitochondrial dysfunction seen in cardiovascular diseases.

The main target for inhibiting mineralocorticoid receptor-mediated signaling in cardiovascular diseases

The main target for inhibiting mineralocorticoid receptor-mediated signaling in cardiovascular diseases

Cardiovascular effects of a novel selective Rho kinase inhibitor, 2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine (DW1865)

The arising critical implications of Rho kinase signaling in cardiovascular diseases have been attracting attention in the pharmacological potential of Rho kinase inhibitors. We identified a novel inhibitor of Rho kinase (2-(1H-indazole-5-yl)amino-4-methoxy-6-piperazino triazine; DW 1865) and characterized its effects in biochemical, cellular, tissue and animal based assays. DW 1865 potently inhibited the kinase activity of both Rho kinase 1 and Rho kinase 2 in vitro, and behaved as an ATP-competitive inhibitor. Interestingly, DW1865 was 10 times more potent in inhibiting Rho kinase activities than fasudil as a selective Rho kinase inhibitor. The activity of DW1865 was shown to be highly selective for Rho kinase in the panel assay of 13 other kinases. In the isolated vascular tissue study, DW1865 exerted vasorelaxation in phenylephrine- or 5-hydroxytriptamine-induced contraction in a concentration-dependent manner manner. In spontaneously hypertensive rats, administration of DW1865 caused a significant and dose-related reduction in blood pressure. Furthermore, DW1865 blocked angiotensin II-induced stress fiber formation and cellular hypertrophy in rat heart-derived H9c2 cells. Taken together, these results suggest that DW1865 is a highly selective and potent Rho kinase inhibitor that will alleviate the pathophysiological actions of Rho kinase such as stress fiber formation, cellular hypertrophy, and hypertension.