title: Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction.
abstract: After myocardial infarction (MI), the heart may undergo progressive ventricular remodeling, resulting in a deterioration of cardiac function. TGF-beta is a key cytokine that both initiates and terminates tissue repair, and its sustained production underlies the development of tissue fibrosis, particularly after MI. We investigated the effects of a novel orally active specific inhibitor of the TGF-beta receptor 1 (SD-208) in an experimental model of MI. Mice underwent ligation of the left coronary artery to induce MI and were subsequently treated for 30 d after infarction with either SD-208 or a vehicle control. Blockade of TGF-beta signaling reduced mean arterial pressure in all groups. SD-208 treatment after MI resulted in a trend for reduced ventricular and renal gene expression of TGF-beta-activated kinase-1 (a downstream modulator of TGF-beta signaling) and a significant decrease in collagen 1, in association with a marked decrease in cardiac mass. Post-MI SD-208 treatment significantly reduced circulating levels of plasma renin activity as well as down-regulating the components of the cardiac and renal renin-angiotensin system (angiotensinogen, angiotensin converting enzyme, and angiotensin II type I receptor). Our findings indicate that blockade of the TGF-beta signaling pathway results in significant amelioration of deleterious cardiac remodeling after infarction.
authors.affiliation: Christchurch Cardioendocrine Research Group, Department of Medicine, Christchurch School of Medicine and Health Sciences, Christchurch 8140, New Zealand. leigh.ellmers@chmeds.ac.nz
authors.forename: Leigh J
authors.initials: LJ
authors.lastname: Ellmers
authors.forename: Nicola J A
authors.initials: NJ
authors.lastname: Scott
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Medicherla
authors.forename: Anna P
authors.initials: AP
authors.lastname: Pilbrow
authors.forename: Paul G
authors.initials: PG
authors.lastname: Bridgman
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Yandle
authors.forename: A Mark
authors.initials: AM
authors.lastname: Richards
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
authors.forename: Vicky A
authors.initials: VA
authors.lastname: Cameron
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011621:Pteridines / Q000494:pharmacology* / Q000627:therapeutic use; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D012083:Renin / Q000097:blood / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D011621:Pteridines; D018125:Receptors, Transforming Growth Factor beta; C511004:SD-208; D016212:Transforming Growth Factor beta; D012083:Renin