An L Moens

Publications

• 4.97

  Impact points

  Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies.

  Yanti Octavia, Carlo G Tocchetti, Kathleen L Gabrielson, Stefan Janssens, Harry J Crijns, An L Moens

  Journal of molecular and cellular cardiology. 03/2012;

  The utility of anthracycline antineoplastic agents in the clinic is compromised by the risk of cardiotoxicity. It has been calculated that approximately 10% of patients treated with doxorubicin or its derivatives will develop cardiac complications up to 10years after the cessation of chemotherapy. O... [more] The utility of anthracycline antineoplastic agents in the clinic is compromised by the risk of cardiotoxicity. It has been calculated that approximately 10% of patients treated with doxorubicin or its derivatives will develop cardiac complications up to 10years after the cessation of chemotherapy. Oxidative stress has been established as the primary cause of cardiotoxicity. However, interventions reducing oxidative stress have not been successful at reducing the incidence of cardiotoxicity in patients treated with doxorubicin. New insights into the cardiomyocyte response to oxidative stress demonstrate that underlying differences between in vitro and in vivo toxicities may modulate the response to superoxide radicals and related compounds. This has led to potentially new uses for pre-existing drugs and new avenues of exploration to find better pharmacotherapies and interventions for the prevention of cardiotoxicity. However, much work still must be done to validate the clinical utility of these new approaches and proposed mechanisms. In this review, the authors have reviewed the molecular mechanisms of the pathogenesis of acute and chronic doxorubicin-induced cardiotoxicity and propose potential pharmacological interventions and treatment options to prevent or reverse this specific type of heart failure.
• 4.40

  Impact points

  Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities.

  Rinrada Kietadisorn, Rio P Juni, An L Moens

  American journal of physiology. Endocrinology and metabolism. 12/2011; 302(5):E481-95.

  Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at m... [more] Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.
• 9.21

  Impact points

  Thrombospondin-4 is required for stretch-mediated contractility augmentation in cardiac muscle.

  Oscar H Cingolani, Jonathan A Kirk, Kinya Seo, Norimichi Koitabashi, Dong-Ik Lee, Genaro Ramirez-Correa, Djahida Bedja, Andreas S Barth, An L Moens, David A Kass

  Circulation research. 12/2011; 109(12):1410-4.

  One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compens... [more] One of the physiological mechanisms by which the heart adapts to a rise in blood pressure is by augmenting myocyte stretch-mediated intracellular calcium, with a subsequent increase in contractility. This slow force response was first described over a century ago and has long been considered compensatory, but its underlying mechanisms and link to chronic adaptations remain uncertain. Because levels of the matricellular protein thrombospondin-4 (TSP4) rapidly rise in hypertension and are elevated in cardiac stress overload and heart failure, we hypothesized that TSP4 is involved in this adaptive mechanism. To determine the mechano-transductive role that TSP4 plays in cardiac regulation to stress. In mice lacking TSP4 (Tsp4⁻/⁻), hearts failed to acutely augment contractility or activate stretch-response pathways (ERK1/2 and Akt) on exposure to acute pressure overload. Sustained pressure overload rapidly led to greater chamber dilation, reduced function, and increased heart mass. Unlike controls, Tsp4⁻/⁻ cardiac trabeculae failed to enhance contractility and cellular calcium after a stretch. However, the contractility response was restored in Tsp4⁻/⁻ muscle incubated with recombinant TSP4. Isolated Tsp4⁻/⁻ myocytes responded normally to stretch, identifying a key role of matrix-myocyte interaction for TSP4 contractile modulation. These results identify TSP4 as myocyte-interstitial mechano-signaling molecule central to adaptive cardiac contractile responses to acute stress, which appears to play a crucial role in the transition to chronic cardiac dilatation and failure.
• 6.08

  Impact points

  NADPH oxidase-dependent oxidative stress in the failing heart: From pathogenic roles to therapeutic approach.

  Yanti Octavia, Hans Peter Brunner-La Rocca, An L Moens

  Free radical biology & medicine. 11/2011; 52(2):291-7.

  Heart failure (HF) occurs when the adaptation mechanisms of the heart fail to compensate for stress factors, such as pressure overload, myocardial infarction, inflammation, diabetes, and cardiotoxic drugs, with subsequent ventricular hypertrophy, fibrosis, myocardial dysfunction, and chamber dilatat... [more] Heart failure (HF) occurs when the adaptation mechanisms of the heart fail to compensate for stress factors, such as pressure overload, myocardial infarction, inflammation, diabetes, and cardiotoxic drugs, with subsequent ventricular hypertrophy, fibrosis, myocardial dysfunction, and chamber dilatation. Oxidative stress, defined as an imbalance between reactive oxygen species (ROS) generation and the capacity of antioxidant defense systems, has been authenticated as a pivotal player in the cardiopathogenesis of the various HF subtypes. The family of NADPH oxidases has been investigated as a key enzymatic source of ROS in the pathogenesis of HF. In this review, we discuss the importance of NADPH oxidase-dependent ROS generation in the various subtypes of HF and its implications. A better understanding of the pathogenic roles of NADPH oxidases in the failing heart is likely to provide novel therapeutic strategies for the prevention and treatment of HF.
• 2.40

  Impact points

  Tackling reperfusion injury after cardiopulmonary bypass with tetrahydrobiopterin: new therapeutic potentials for this phenylketonuria drug?

  Yanti Octavia, Natascha L Assman, An L Moens

  European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 09/2011; 41(1):233-4.
• 2.83

  Impact points

  Role of sepiapterin on endothelial nitric oxide synthase in acute kidney injury: an enigmatic story.

  Rio P Juni, An L Moens

  Journal of cardiovascular pharmacology. 09/2011; 58(3):335; author reply 335-336.
• 3.73

  Impact points

  Endothelial dysfunction after right coronary artery remodeling: a new pathogenetic role of eNOS uncoupling?

  Yanti Octavia, Kirstin Wingler, Harald H Schmidt, An L Moens

  Journal of applied physiology (Bethesda, Md. : 1985). 07/2011; 111(1):329; author reply 330.
• 5.80

  Impact points

  Is NOS uncoupling the missing link between atrial fibrillation and chronic non-ischaemic cardiomyopathy?

  Harry J Crijns, Ulrich Schotten, An L Moens

  Cardiovascular research. 06/2011; 91(3):556; author reply 557-8.
• 4.97

  Impact points

  Bi-modal dose-dependent cardiac response to tetrahydrobiopterin in pressure-overload induced hypertrophy and heart failure.

  An L Moens, Elizabeth A Ketner, Eiki Takimoto, Tim S Schmidt, Charles A O'Neill, Michael S Wolin, Nicholas J Alp, Keith M Channon, David A Kass

  Journal of molecular and cellular cardiology. 05/2011; 51(4):564-9.

  The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-c... [more] The exogenous administration of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase (NOS), has been shown to reduce left ventricular hypertrophy, fibrosis, and cardiac dysfunction in mice with pre-established heart disease induced by pressure-overload. In this setting, BH4 re-coupled endothelial NOS (eNOS), with subsequent reduction of NOS-dependent oxidative stress and reversal of maladaptive remodeling. However, recent studies suggest the effective BH4 dosing may be narrower than previously thought, potentially due to its oxidation upon oral consumption. Accordingly, we assessed the dose response of daily oral synthetic sapropterin dihydrochloride (6-R-l-erythro-5,6,7,8-tetrahydrobiopterin, 6R-BH4) on pre-established pressure-overload cardiac disease. Mice (n=64) were administered 0-400mg/kg/d BH4 by ingesting small pre-made pellets (consumed over 15-30 min). In a dose range of 36-200mg/kg/d, 6R-BH4 suppressed cardiac chamber remodeling, hypertrophy, fibrosis, and oxidative stress with pressure-overload. However, at both lower and higher doses, BH4 had less or no ameliorative effects. The effective doses correlated with a higher myocardial BH4/BH2 ratio. However, BH2 rose linearly with dose, and at the 400mg/kg/d, this lowered the BH4/BH2 ratio back toward control. These results expose a potential limitation for the clinical use of BH4, as variability of cellular redox and perhaps heart disease could produce a variable therapeutic window among individuals. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
• 3.71

  Impact points

  Modulating endothelial nitric oxide synthase: a new cardiovascular therapeutic strategy.

  Yixuan Zhang, Stefan P Janssens, Kirstin Wingler, Harald H H W Schmidt, An L Moens

  American journal of physiology. Heart and circulatory physiology. 05/2011; 301(3):H634-46.

  The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a... [more] The pathogenesis of many cardiovascular diseases is associated with reduced nitric oxide (NO) bioavailability and/or increased endothelial NO synthase (eNOS)-dependent superoxide formation. These findings support that restoring and conserving adequate NO signaling in the heart and blood vessels is a promising therapeutic intervention. In particular, modulating eNOS, e.g., through increasing the bioavailability of its substrate and cofactors, enhancing its transcription, and interfering with other modulators of eNOS pathway, such as netrin-1, has a high potential for effective treatments of cardiovascular diseases. This review provides an overview of the possibilities for modulating eNOS and how this may be translated to the clinic in addition to describing the genetic models used to study eNOS modulation.
• 3.37

  Impact points

  Folic acid says NO to endothelial dysfunction in patients with metabolic syndrome.

  Henri J Boersma, An L Moens

  Obesity (Silver Spring, Md.). 05/2011; 19(5):895-6.
• 6.08

  Impact points

  Pathogenetic role of eNOS uncoupling in cardiopulmonary disorders.

  Jan F Gielis, Judy Y Lin, Kirstin Wingler, Paul E Y Van Schil, Harald H Schmidt, An L Moens

  Free radical biology & medicine. 04/2011; 50(7):765-76.

  The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of ath... [more] The homodimeric flavohemeprotein endothelial nitric oxide synthase (eNOS) oxidizes l-arginine to l-citrulline and nitric oxide (NO), which acutely vasodilates blood vessels and inhibits platelet aggregation. Chronically, eNOS has a major role in the regulation of blood pressure and prevention of atherosclerosis by decreasing leukocyte adhesion and smooth muscle proliferation. However, a disturbed vascular redox balance results in eNOS damage and uncoupling of oxygen activation from l-arginine conversion. Uncoupled eNOS monomerizes and generates reactive oxygen species (ROS) rather than NO. Indeed, eNOS uncoupling has been suggested as one of the main pathomechanisms in a broad range of cardiovascular and pulmonary disorders such as atherosclerosis, ventricular remodeling, and pulmonary hypertension. Therefore, modulating uncoupled eNOS, in particular eNOS-dependent ROS generation, is an attractive therapeutic approach to preventing and/or treating cardiopulmonary disorders, including protective effects during cardiothoracic surgery. This review provides a comprehensive overview of the pathogenetic role of uncoupled eNOS in both cardiovascular and pulmonary disorders. In addition, the related therapeutic possibilities such as supplementation with the eNOS substrate l-arginine, volatile NO, and direct NO donors as well as eNOS modulators such as the eNOS cofactor tetrahydrobiopterin and folic acid are discussed in detail.
• 4.40

  Impact points

  Role of tetrahydrobiopterin (BH4) in hyperhomocysteinemia-induced endothelial dysfuction: new indication for this orphan-drug?

  Rinrada Kietadisorn, Bas L Kietselaer, Harald H H W Schmidt, An L Moens

  American journal of physiology. Endocrinology and metabolism. 03/2011; 300(6):E1176; author reply E1177-8.

  n/a.
• 4.59

  Impact points

  Folic acid enlarges the armamentarium for the treatment of coronary vasospasm.

  Rio P Juni, Henk J Blom, Harald H Schmidt, An L Moens

  Journal of cellular physiology. 03/2011;
• 4.97

  Impact points

  Targeting endothelial and myocardial dysfunction with tetrahydrobiopterin.

  An L Moens, Rinrada Kietadisorn, Judy Y Lin, David Kass

  Journal of molecular and cellular cardiology. 03/2011; 51(4):559-63.

  Tetrahydrobiopterin (BH(4)) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase (NOS) isoforms. It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species. Experimental studies in humans and anim... [more] Tetrahydrobiopterin (BH(4)) is an essential cofactor for aromatic amino acid hydroxylases and for all three nitric oxide synthase (NOS) isoforms. It also has a protective role in the cell as an antioxidant and scavenger of reactive nitrogen and oxygen species. Experimental studies in humans and animals demonstrate that decreased BH(4)-bioavailability, with subsequent uncoupling of endothelial NOS (eNOS) plays an important role in the pathogenesis of endothelial dysfunction, hypertension, ischemia-reperfusion injury, and pathologic cardiac remodeling. Synthetic BH(4) is clinically approved for the treatment of phenylketonuria, and experimental studies support its capacity for ameliorating cardiovascular pathophysiologies. To date, however, the translation of these studies to human patients remains limited, and early results have been mixed. In this review, we discuss the pathophysiologic role of decreased BH(4) bioavailability, molecular mechanisms regulating its metabolism, and its potential therapeutic use as well as pitfalls as an NOS-modulating drug. This article is part of a special issue entitled ''Key Signaling Molecules in Hypertrophy and Heart Failure.''
• 4.97

  Impact points

  Modulating iNOS-uncoupling: a new therapeutic avenue to tackle reperfusion-injury?

  Rio P Juni, An L Moens

  Journal of molecular and cellular cardiology. 02/2011; 50(5):924.
• 3.71

  Impact points

  Tetrahydrobiopterin and hypertension: more than an emigrating story.

  Judy Y Lin, An L Moens

  American journal of physiology. Heart and circulatory physiology. 01/2011; 300(3):H715.

  n/a.
• 3.58

  Impact points

  Folic Acid as a cardiovascular drug: dose matters.

  Rinrada Kietadisorn, Harald H Schmidt, An L Moens

  The American journal of cardiology. 12/2010; 106(11):1673-4.
• 3.71

  Impact points

  Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process.

  Willem A den Hengst, Jan F Gielis, Judy Y Lin, Paul E Van Schil, Leon J De Windt, An L Moens

  American journal of physiology. Heart and circulatory physiology. 11/2010; 299(5):H1283-99.

  Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are mor... [more] Lung ischemia-reperfusion injury remains one of the major complications after cardiac bypass surgery and lung transplantation. Due to its dual blood supply system and the availability of oxygen from alveolar ventilation, the pathogenetic mechanisms of ischemia-reperfusion injury in the lungs are more complicated than in other organs, where loss of blood flow automatically leads to hypoxia. In this review, an extensive overview is given of the molecular and cellular mechanisms that are involved in the pathogenesis of lung ischemia-reperfusion injury and the possible therapeutic strategies to reduce or prevent it. In addition, the roles of neutrophils, alveolar macrophages, cytokines, and chemokines, as well as the alterations in the cell-death related pathways, are described in detail.
• 4.97

  Impact points

  Beta 3-adrenoreceptor regulation of nitric oxide in the cardiovascular system.

  An L Moens, Ronghua Yang, Vabren L Watts, Lili A Barouch

  Journal of molecular and cellular cardiology. 02/2010; 48(6):1088-95.

  The presence of a third beta-adrenergic receptor (beta 3-AR) in the cardiovascular system has challenged the classical paradigm of sympathetic regulation by beta1- and beta2-adrenergic receptors. While beta 3-AR's role in the cardiovascular system remains controversial, increasing evidence sugge... [more] The presence of a third beta-adrenergic receptor (beta 3-AR) in the cardiovascular system has challenged the classical paradigm of sympathetic regulation by beta1- and beta2-adrenergic receptors. While beta 3-AR's role in the cardiovascular system remains controversial, increasing evidence suggests that it serves as a "brake" in sympathetic overstimulation - it is activated at high catecholamine concentrations, producing a negative inotropic effect that antagonizes beta1- and beta2-AR activity. The anti-adrenergic effects induced by beta 3-AR were initially linked to nitric oxide (NO) release via endothelial NO synthase (eNOS), although more recently it has been shown under some conditions to increase NO production in the cardiovascular system via the other two NOS isoforms, namely inducible NOS (iNOS) and neuronal NOS (nNOS). We summarize recent findings regarding beta 3-AR effects on the cardiovascular system and explore its prospective as a therapeutic target, particularly focusing on its emerging role as an important mediator of NO signaling in the pathogenesis of cardiovascular disorders.