Decreased soluble guanylate cyclase contributes to cardiac dysfunction induced by chronic doxorubicin treatment in mice

Aims: The use of doxorubicin, a potent chemotherapeutic agent, is limited by cardiotoxicity. We tested the hypothesis that decreased soluble guanylate cyclase (sGC) enzyme activity contributes to the development of doxorubicin-induced cardiotoxicity. Results: Doxorubicin administration (20 mg/kg, intraperitoneally [IP]) reduced cardiac sGC activity in wild-type (WT) mice. To investigate whether decreased sGC activity contributes to doxorubicin-induced cardiotoxicity, we studied mice with cardiomyocyte-specific deficiency of the sGC alpha 1-subunit (mice with cardiomyocyte-specific deletion of exon 6 of the sGC alpha 1 allele [sGC alpha 1(-/-CM)]). After 12 weeks of doxorubicin administration (2 mg/kg/week IP), left ventricular (LV) systolic dysfunction was greater in sGC alpha 1(-/-CM) than WT mice. To further assess whether reduced sGC activity plays a pathogenic role in doxorubicin-induced cardiotoxicity, we studied a mouse model in which decreased cardiac sGC activity was induced by cardiomyocyte-specific expression of a dominant negative sGC alpha 1 mutant (DNsGC alpha 1) upon doxycycline removal (Tet-off). After 8 weeks of doxorubicin administration, DNsGC alpha 1(tg/+), but not WT, mice displayed LV systolic dysfunction and dilatation. The difference in cardiac function and remodeling between DNsGC alpha 1(tg/+) and WT mice was even more pronounced after 12 weeks of treatment. Further impairment of cardiac function was attenuated when DNsGC alpha 1 gene expression was inhibited (beginning at 8 weeks of doxorubicin treatment) by administering doxycycline. Furthermore, doxorubicin-associated reactive oxygen species generation was higher in sGC alpha 1-deficient than WT hearts. Innovation and Conclusion: These data demonstrate that a reduction in cardiac sGC activity worsens doxorubicin-induced cardiotoxicity in mice and identify sGC as a potential therapeutic target. Various pharmacological sGC agonists are in clinical development or use and may represent a promising approach to limit doxorubicin-associated cardiotoxicity

Nitric Oxide For Inhalation Reduces Left Ventricular Remodeling After Myocardial Infarction In Pigs

Liu X., Pokreisz P., Gheysens O., Ghysels S., Maes F., Caluwe E., Gillijns H., Pellens M., Verbeken E., Bogaert J., Van de Werf F., Bloch K.D., Janssens S., ''Nitric oxide for inhalation reduces left ventricular remodeling after myocardial infarction in pigs'', Circulation, vol. 118, no. 18, suppl. 2, pp. S547, October 2008 (American Heart Association scientific sessions 2008, November 8-12, 2008, New Orleans, LA, USA).status: publishe

Placental growth factor increases regional myocardial blood flow and function in a new porcine model of chronic myocardial ischemia

Liu X., Caluwe E., Reyns G., Verhamme P., Pokreisz P., Vandenwijngaert S., Dubois C., Zalewski J., Ghysels S., Maes F., Gillijns H., Pellens M., Vanden Driessche N., Patel A., Van de Werf F., Verbeken E., Bogaert J., Janssens S., ''Placental growth factor increases regional myocardial blood flow and function in a new porcine model of chronic myocardial ischemia'', Circulation, vol. 120, no. 18, suppl., pp. S837, November 2009 (American Heart Association scientific sessions 2009, November 14-18, 2009, Orlando, Florida, USA).status: publishe

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

Blood outgrowth endothelial cells (BOECs) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of BOECs from patients with ischemic cardiomyopathy (ICMP) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of BOECs derived from ICMP with BOECs from age-matched (ACON) and healthy young (CON) controls.Dauwe D., Pelacho B., Wibowo A., Walravens A., Verdonck K., Gillijns H., Caluwe E., Pokreisz P., van Gastel N., Carmeliet G., Depypere M., Maes F., Vanden Driessche N., Droogne W., Van Cleemput J., Vanhaecke J., Prosper F., Verfaillie C., Luttun A., Janssens S., ''Neovascularization potential of blood outgrowth endothelial cells from Patients with stable ischemic heart failure is preserved'', Journal of the American Heart Association, vol. 5, no. 4, pp. e002288, April 2016.status: publishe

Endothelial Zeb2 preserves the hepatic angioarchitecture and protects against liver fibrosis

Aims Hepatic capillaries are lined with specialized liver sinusoidal endothelial cells (LSECs) which support macromolecule passage to hepatocytes and prevent fibrosis by keeping hepatic stellate cells (HSCs) quiescent. LSEC specialization is co-determined by transcription factors. The zinc-finger E-box-binding homeobox (Zeb)2 transcription factor is enriched in LSECs. Here, we aimed to elucidate the endothelium-specific role of Zeb2 during maintenance of the liver and in liver fibrosis. Methods and results To study the role of Zeb2 in liver endothelium we generated EC-specific Zeb2 knock-out (ECKO) mice. Sequencing of liver EC RNA revealed that deficiency of Zeb2 results in prominent expression changes in angiogenesis-related genes. Accordingly, the vascular area was expanded and the presence of pillars inside ECKO liver vessels indicated that this was likely due to increased intussusceptive angiogenesis. LSEC marker expression was not profoundly affected and fenestrations were preserved upon Zeb2 deficiency. However, an increase in continuous EC markers suggested that Zeb2-deficient LSECs are more prone to dedifferentiation, a process called ‘capillarization’. Changes in the endothelial expression of ligands that may be involved in HSC quiescence together with significant changes in the expression profile of HSCs showed that Zeb2 regulates LSEC–HSC communication and HSC activation. Accordingly, upon exposure to the hepatotoxin carbon tetrachloride (CCl4), livers of ECKO mice showed increased capillarization, HSC activation, and fibrosis compared to livers from wild-type littermates. The vascular maintenance and anti-fibrotic role of endothelial Zeb2 was confirmed in mice with EC-specific overexpression of Zeb2, as the latter resulted in reduced vascularity and attenuated CCl4-induced liver fibrosis. Conclusion Endothelial Zeb2 preserves liver angioarchitecture and protects against liver fibrosis. Zeb2 and Zeb2-dependent genes in liver ECs may be exploited to design novel therapeutic strategies to attenuate hepatic fibrosis