Gene delivery of sarcoplasmic reticulum calcium ATPase inhibits ventricular remodeling in ischemic mitral regurgitation.
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.
Beeri
Ronen
R
Cardiac Ultrasound Laboratory and Cardiac Surgery Department, Heart Center, Massachusetts General Hospital, Boston, Mass 02114, USA.
Chaput
Miguel
M
Guerrero
J Luis
JL
Kawase
Yoshiaki
Y
Yosefy
Chaim
C
Abedat
Suzan
S
Karakikes
Ioannis
I
Morel
Charlotte
C
Tisosky
Ashley
A
Sullivan
Suzanne
S
Handschumacher
Mark D
MD
Gilon
Dan
D
Vlahakes
Gus J
GJ
Hajjar
Roger J
RJ
Levine
Robert A
RA
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*
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases