title: Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricular remodeling in ischemic mitral regurgitation.
abstract: BACKGROUND
  Mitral regurgitation (MR) doubles mortality after myocardial infarction (MI). We have demonstrated that MR worsens remodeling after MI and that early correction reverses remodeling. Sarcoplasmic reticulum Ca(+2)-ATPase (SERCA2a) is downregulated in this process. We hypothesized that upregulating SERCA2a might inhibit remodeling in a surgical model of apical MI (no intrinsic MR) with independent MR-type flow.
  
  
  RESULTS
  In 12 sheep, percutaneous gene delivery was performed by using a validated protocol to perfuse both the left anterior descending and circumflex coronary arteries with occlusion of venous drainage. We administered adeno-associated virus 6 (AAV6) carrying SERCA2a under a Cytomegalovirus promoter control in 6 sheep and a reporter gene in 6 controls. After 2 weeks, a standardized apical MI was created, and a shunt was implanted between the left ventricle and left atrium, producing regurgitant fractions of ≈30%. Animals were compared at baseline and 1 and 3 months by 3D echocardiography, Millar hemodynamics, and biopsies. The SERCA2a group had a well-maintained preload-recruitable stroke work at 3 months (decrease by 8±10% vs 42±12% with reporter gene controls; P<0.001). Left ventricular dP/dt followed the same pattern (no change vs 55% decrease; P<0.001). Left ventricular end-systolic volume was lower with SERCA2a (82.6±9.6 vs 99.4±9.7 mL; P=0.03); left ventricular end-diastolic volume, reflecting volume overload, was not significantly different (127.8±6.2 vs 134.3±9.4 mL). SERCA2a sheep showed a 15% rise in antiapoptotic pAkt versus a 30% reduction with the reporter gene (P<0.001). Prohypertrophic activated STAT3 was also 41% higher with SERCA2a than in controls (P<0.001). Proapoptotic activated caspase-3 rose >5-fold during 1 month in both SERCA2a and control animals (P=NS) and decreased by 19% at 3 months, remaining elevated in both groups.
  
  
  CONCLUSIONS
  In this controlled model, upregulating SERCA2a induced better function and lesser remodeling, with improved contractility, smaller volume, and activation of prohypertrophic/antiapoptotic pathways. Although caspase-3 remained activated in both groups, SERCA2a sheep had increased molecular antiremodeling "tone." We therefore conclude that upregulating SERCA2a inhibits MR-induced post-MI remodeling in this model and thus may constitute a useful approach to reduce the vicious circle of remodeling in ischemic MR.
authors.affiliation: Cardiac Ultrasound Laboratory and Cardiac Surgery Department, Heart Center, Massachusetts General Hospital, Boston, Mass 02114, USA.
authors.forename: Ronen
authors.initials: R
authors.lastname: Beeri
authors.forename: Miguel
authors.initials: M
authors.lastname: Chaput
authors.forename: J Luis
authors.initials: JL
authors.lastname: Guerrero
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Chaim
authors.initials: C
authors.lastname: Yosefy
authors.forename: Suzan
authors.initials: S
authors.lastname: Abedat
authors.forename: Ioannis
authors.initials: I
authors.lastname: Karakikes
authors.forename: Charlotte
authors.initials: C
authors.lastname: Morel
authors.forename: Ashley
authors.initials: A
authors.lastname: Tisosky
authors.forename: Suzanne
authors.initials: S
authors.lastname: Sullivan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Handschumacher
authors.forename: Dan
authors.initials: D
authors.lastname: Gilon
authors.forename: Gus J
authors.initials: GJ
authors.lastname: Vlahakes
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.forename: Robert A
authors.initials: RA
authors.lastname: Levine
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D000229:Dependovirus; D004195:Disease Models, Animal; D018618:Echocardiography, Doppler, Color; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D008944:Mitral Valve Insufficiency / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D017202:Myocardial Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D011401:Promoter Regions, Genetic; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D012756:Sheep; D015854:Up-Regulation; D020257:Ventricular Remodeling / Q000235:genetics* / Q000502:physiology*
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases