Stefan P Janssens

Publications of Stefan P Janssens

• Cardiac bone marrow cell therapy: the proof of the pudding remains in the eating.

  Authors: Stefan P Janssens

  European heart journal. 06/2011; 32(14):1697-700.

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

  Authors: 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. TheseThe 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.

• Granulocyte colony-stimulating factor in cardiac repair: time for a reappraisal?

  Authors: Stefan P Janssens

  European journal of heart failure. 10/2010; 12(10):1021-3.

• Cardioselective nitric oxide synthase 3 gene transfer protects against myocardial reperfusion injury.

  Authors: Zsolt Szelid, Peter Pokreisz, Xiaoshun Liu, Pieter Vermeersch, Glenn Marsboom, Hilde Gillijns, Marijke Pellens, Erik Verbeken, Frans Van de Werf, Desire Collen, Stefan P Janssens

  Basic research in cardiology. 12/2009;

  Nitric oxide modulates the severity of myocardial ischemia-reperfusion (I/R) injury. We investigated whether cardioselective nitric oxide synthase 3 (NOS3) gene transfer could confer myocardialNitric oxide modulates the severity of myocardial ischemia-reperfusion (I/R) injury. We investigated whether cardioselective nitric oxide synthase 3 (NOS3) gene transfer could confer myocardial protection against I/R injury in pigs and examined potential molecular mechanisms. I/R injury was induced by balloon occlusion of the left anterior descending artery for 45 min followed by 4 or 72 h reperfusion. Hemodynamic and pathological changes were measured in pigs in the absence (n = 11) or presence of prior intracoronary retroinfusion of human NOS3 (AdNOS3, 5 x 10(10) PFU, n = 13) or control vector (AdRR5, 5 x 10(10) PFU, n = 11). Retrograde NOS3 gene transfer selectively increased NOS3 expression and NO bioavailability in the area at risk (AAR) without changing endogenous NOS isoform expression. At 4 h R, LV systolic (dP/dt (max)) and diastolic (dP/dt (min)) function was better preserved in AdNOS3- than in AdRR5-injected pigs (2,539 +/- 165 vs. 1,829 +/- 156 mmHg/s, and -2,781 +/- 340 vs. -2,062 +/- 292 mmHg/s, respectively, P < 0.05 for both). Myocardial infarct size (% AAR) was significantly smaller in AdNOS3 than in control and AdRR5 and associated with a significantly greater reduction in cardiac myeloperoxidase activity, a marker of neutrophil infiltration. The latter effects were sustained at 72 h R in a subset of pigs (n = 7). In the AAR, intercellular endothelial adhesion molecule-1 expression and cardiomyocyte apoptosis were significantly lower in AdNOS3. In conclusion, single myocardial NOS3 retroinfusion attenuates I/R injury, and causes a sustained reduction in myocardial infarct size and inflammatory cell infiltration. Gene-based strategies to increase NO bioavailability may have therapeutic potential in myocardial I/R.

• Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice.

  Authors: Peter Pokreisz, Sara Vandenwijngaert, Virginie Bito, An Van den Bergh, Ilse Lenaerts, Cornelius Busch, Glenn Marsboom, Olivier Gheysens, Pieter Vermeersch, Liesbeth Biesmans [......] Marijke Pellens, Alfons Van Lommel, Emmanuel Buys, Luc Schoonjans, Johan Vanhaecke, Erik Verbeken, Karin Sipido, Paul Herijgers, Kenneth D Bloch, Stefan P Janssens

  Circulation. 02/2009;

  BACKGROUND: -Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricularBACKGROUND: -Ventricular expression of phosphodiesterase-5 (PDE5), an enzyme responsible for cGMP catabolism, is increased in human right ventricular hypertrophy, but its role in left ventricular (LV) failure remains incompletely understood. We therefore measured LV PDE5 expression in patients with advanced systolic heart failure and characterized LV remodeling after myocardial infarction in transgenic mice with cardiomyocyte-specific overexpression of PDE5 (PDE5-TG). Methods and Results-Immunoblot and immunohistochemistry techniques revealed that PDE5 expression was greater in explanted LVs from patients with dilated and ischemic cardiomyopathy than in control hearts. To evaluate the impact of increased ventricular PDE5 levels on cardiac function, PDE5-TG mice were generated. Confocal and immunoelectron microscopy revealed increased PDE5 expression in cardiomyocytes, predominantly localized to Z-bands. At baseline, myocardial cGMP levels, cell shortening, and calcium handling in isolated cardiomyocytes and LV hemodynamic measurements were similar in PDE5-TG and wild-type littermates. Ten days after myocardial infarction, LV cGMP levels had increased to a greater extent in wild-type mice than in PDE5-TG mice (P<0.05). Ten weeks after myocardial infarction, LV end-systolic and end-diastolic volumes were larger in PDE5-TG than in wild-type mice (57+/-5 versus 39+/-4 and 65+/-6 versus 48+/-4 microL, respectively; P<0.01 for both). LV systolic dysfunction and diastolic dysfunction were more marked in PDE5-TG than in wild-type mice, associated with enhanced hypertrophy and reduced contractile function in isolated cardiomyocytes from remote myocardium. Conclusions-Increased PDE5 expression predisposes mice to adverse LV remodeling after myocardial infarction. Increased myocardial PDE5 expression in patients with advanced cardiomyopathy may contribute to the development of heart failure and represents an important therapeutic target.

• How old is your heart?

  Authors: Karin R Sipido, Stefan P Janssens

  Circulation research. 09/2007; 101(4):323-5.

• Disruption of nitric oxide synthase 3 protects against the cardiac injury, dysfunction, and mortality induced by doxorubicin.

  Authors: Tomas G Neilan, Sarah L Blake, Fumito Ichinose, Michael J Raher, Emmanuel S Buys, Davinder S Jassal, Elissa Furutani, Teresa Miriam Perez-Sanz, Amanda Graveline, Stefan P Janssens, Michael H Picard, Marielle Scherrer-Crosbie, Kenneth D Bloch

  Circulation. 08/2007; 116(5):506-14.

  BACKGROUND: Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoproteinBACKGROUND: Flavoprotein reductases are involved in the generation of reactive oxygen species by doxorubicin. The objective of the present study was to determine whether or not one flavoprotein reductase, endothelial nitric oxide synthase (nitric oxide synthase 3 [NOS3]), contributes to the cardiac dysfunction and injury seen after the administration of doxorubicin. METHODS AND RESULTS: A single dose of doxorubicin (20 mg/kg) was administered to wild-type (WT) mice, NOS3-deficient mice (NOS3-/-), and mice with cardiomyocyte-specific overexpression of NOS3 (NOS3-TG). Cardiac function was assessed after 5 days with the use of echocardiography. Doxorubicin decreased left ventricular fractional shortening from 57+/-2% to 47+/-1% (P<0.001) in WT mice. Compared with WT mice, fractional shortening was greater in NOS3-/- and less in NOS3-TG after doxorubicin (55+/-1% and 35+/-2%; P<0.001 for both). Cardiac tissue was harvested from additional mice at 24 hours after doxorubicin administration for measurement of cell death and reactive oxygen species production. Doxorubicin induced cardiac cell death and reactive oxygen species production in WT mice, effects that were attenuated in NOS3-/- and were more marked in NOS3-TG mice. Finally, WT and NOS3-/- mice were treated with a lower dose of doxorubicin (4 mg/kg) administered weekly over 5 weeks. Sixteen weeks after beginning doxorubicin treatment, fractional shortening was greater in NOS3-/- than in WT mice (45+/-2% versus 28+/-1%; P<0.001), and mortality was reduced (7% versus 60%; P<0.001). CONCLUSIONS: These findings implicate NOS3 as a key mediator in the development of left ventricular dysfunction after administration of doxorubicin.

• Applied gene therapy in preclinical models of vascular injury.

  Authors: Stefan P Janssens

  Current atherosclerosis reports. 06/2003; 5(3):186-90.

  Atherosclerosis remains the major cause of morbidity and mortality in Western countries. Atherothrombotic complications, including vascular occlusions and severe narrowing of nutrient blood vesselsAtherosclerosis remains the major cause of morbidity and mortality in Western countries. Atherothrombotic complications, including vascular occlusions and severe narrowing of nutrient blood vessels in the cerebral, coronary, or peripheral circulation, usually require invasive revascularization strategies. As molecular mediators contributing to these complications are being identified in more representative experimental injury models, and as gene transfer platforms and vectors acquire improved safety and efficacy profiles, there is ground for cautious optimism that gene-based interventions will likely reduce the clinical burden of these diseases. Increased generation of reactive oxygen species in diseased atherosclerotic vessels has been implicated in vasospasm, exaggerated neointima formation, and enhanced thrombosis. Ex vivo pressurized vascular gene transfer in venous bypass grafts using antisense oligonucleotides directed against cell-cycle control genes can modify the venous graft's phenotype and confer clinical benefit with improved long-term graft survival. Alternatively, percutaneous intra-arterial gene transfer is feasible, but at relatively low transgene expression levels. Although this may suffice in the case of secreted gene products with marked paracrine or bystander effects, including nitric oxide synthase and heme oxygenase-1, drug- and gene-eluting stents may provide the preferred future vehicle for well-controlled, quantifiable, and safe vascular gene transfer. Continued efforts to improve gene transfer technology in diseased human vessels and to increase our understanding of molecular targets are required before the full therapeutic potential of vascular gene therapy can be realized.

• Defining gene transfer before expecting gene therapy: putting the horse before the cart.

  Authors: Sorin Pislaru, Stefan P Janssens, Bernard J Gersh, Robert D Simari

  Circulation. 08/2002; 106(5):631-6.