title: Inhibition of SMAD2 phosphorylation preserves cardiac function during pressure overload.
abstract: OBJECTIVE
  Left ventricular (LV) pressure overload leads to myocardial remodelling and reduced cardiac function. Both cardioprotective and deleterious effects have been attributed to SMAD2/3 (SMAD, small mothers against decapentaplegic) signalling, but the role of these important molecules in pressure overload remains unclear. The aim of this study was to examine the effects of SMAD2 inhibition on cardiac function and remodelling in mice subjected to aortic banding (AB), using a small molecule inhibitor (SM16) of SMAD2 signalling.
  
  
  RESULTS
  C57BL/6 mice were subjected to 1 week of AB, which led to a three-fold increased phosphorylation of SMAD2 that was reduced by SM16 (P≤ 0.05), as measured by western blotting. Cardiac function was evaluated by echocardiography and was preserved by SM16, as fractional shortening was increased by 38% (P≤ 0.05) and mitral flow deceleration reduced by 28% compared with AB mice not receiving SM16 (P≤ 0.05). In accordance with this, SM16 abolished the 21% increase in lung weight in AB mice (P≤ 0.05). Cardiomyocyte hypertrophy and foetal gene expression, as measured by qPCR, were also reduced. Myocardial collagen protein was unaltered 1 week after AB. LV sarcoplasmic reticulum Ca(2+)ATPase (SERCA2) reduction in AB mice and in transforming growth factor-β1-stimulated rat cardiomyocytes was diminished by SM16. Ca(2+) transient decay kinetics were improved in cardiomyocytes isolated from AB mice receiving SM16.
  
  
  CONCLUSIONS
  In pressure overload, pharmacological inhibition of SMAD2 signalling attenuated cardiomyocyte hypertrophy and preserved cardiac function. SM16 prevented SMAD2-mediated downregulation of SERCA2 in vivo and in cardiomyocytes, suggesting improved cardiomyocyte Ca(2+) handling as a possible cardioprotective mechanism.
authors: Department of Cardiothoracic Surgery, Oslo University Hospital Ullevål, Norway.
authors: Johannes L
authors: JL
authors: Bjørnstad
authors: Biljana
authors: B
authors: Skrbic
authors: Henriette S
authors: HS
authors: Marstein
authors: Almira
authors: A
authors: Hasic
authors: Ivar
authors: I
authors: Sjaastad
authors: William E
authors: WE
authors: Louch
authors: Geir
authors: G
authors: Florholmen
authors: Geir
authors: G
authors: Christensen
authors: Theis
authors: T
authors: Tønnessen
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D049108:Cell Enlargement / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics; D055436:Growth Differentiation Factor 15 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D000199:Actins; D053961:Azabicyclo Compounds; D055436:Growth Differentiation Factor 15; D012333:RNA, Messenger; C528106:SM16 compound; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D018995:Myosin Heavy Chains; C506947:Atp2a2 protein, mouse