title: A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re-vascularization.
abstract: BACKGROUND
  Rescuing adverse myocardial remodeling is an unmet clinical goal and, correspondingly, pharmacological means for its intended reversal are urgently needed.
  
  
  OBJECTIVE
  To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling.
  
  
  RESULTS
  A VEGF-based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure. Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy, enlarged LV size and improve cardiac function was monitored. Arguing for clinical relevance of the experimental system, clinically-used drugs operating on the Renin-Angiotensin-Aldosterone-System (RAAS), namely, the ACE inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling. Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return. Similarly, the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature. Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS, a specific inhibitor of 11β-hydroxy-steroid dehydrogenase type 1 (11β HSD1), a key enzyme required for generating active glucocorticoids, fully rescued myocardial hypertrophy. This was associated with mitigating the hypertrophy-associated gene signature, including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal.
  
  
  CONCLUSIONS
  A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action, exemplified here by uncoupling their vascular affects.
authors.affiliation: Departments of Developmental Biology and Cancer Research, The Hebrew University-Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Gordon
authors.affiliation: Departments of Developmental Biology and Cancer Research, The Hebrew University-Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Cardiology, The Hebrew University-Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.affiliation: Department of Metabolic and Vascular Disease, Hoffmann-La Roche Pharmaceuticals, Basel, Switzerland.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gruener
authors.affiliation: Department of Metabolic and Vascular Disease, Hoffmann-La Roche Pharmaceuticals, Basel, Switzerland.
authors.forename: Sherrie
authors.initials: S
authors.lastname: Pietranico-Cole
authors.affiliation: Department of Cardiology, The Hebrew University-Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Oppenheim
authors.affiliation: Departments of Developmental Biology and Cancer Research, The Hebrew University-Hadassah University Hospital, Jerusalem, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Keshet
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1