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. Author manuscript; available in PMC: 2012 Sep 16.

Published in final edited form as: Nature. 2011 Sep 7;477(7366):601–605. doi: 10.1038/nature10407

(a) Heart morphology, cardiac function, and heart dimensions were examined in mice injected with 5 × 10¹⁰ vg of rAAVs at 6 weeks after injection. Representative gross images of the hearts (top left panel), hematoxylin and eosin staining results (top right panel), and M-mode imaging data (bottom panel) are shown.

(b) Quantifications of the LV internal diameters in end-diastole (LVIDd) and end-systole (LVIDs) and the fractional shortening (FS) and ejection fraction (EF) by echocardiography in rAAV9/shSC or rAAV9/shSUMO1 injected mice (5 × 10¹⁰ vg/mice per each group, n=14 per each group).

(c) Survival of animals following rAAV9-mediated cardiac knockdown of SUMO1.The Kaplan-Meier curves are shown for different doses of rAAV9/ shSUMO1 (n=14 per each group) or rAAV9/shSC (5 × 10¹⁰ vg/mice, n=24).

(d) Representative immunoblot analysis for the indicated cardiac proteins are shown from samples collected 6 weeks after tail-vein injection with rAAV9/shSC (5 × 10¹⁰ vg/mice, n=4) or rAAV9/shSUMO1 (5 × 10¹⁰ vg/mice, n=7) (left panel). Quantification of GAPDH corrected cardiac protein immunoblot signals (right panel).

(e) Ca²⁺-dependence of SERCA2a’s ATPase activity. The ATPase activity was examined in preparations from scramble (●) injected and SUMO1 shRNA () injected hearts (5 × 10¹⁰ vg/mice per each group, n=3 per each group).

All data represent the mean ± the SD. * p < 0.05; ** p < 0.001 vs. the respective control as determined using Student’s t-test. NS: non-significant.

(f) A working model for the regulation of SERCA2a function by SUMOylation. Under basal conditions, SUMOylation enhances SERCA2a’s protein stability and its Ca²⁺ pump function to regulate cardiac contractility. However, increased levels of unSUMOylated SERCA2a due to low SUMO1 protein pools triggers impaired SERCA2a activity and induces cardiac dysfunction under pathophysiological conditions.

Inline graphic — (a) Heart morphology, cardiac function, and heart dimensions were examined in mice injected with 5 × 10¹⁰ vg of rAAVs at 6 weeks after injection. Representative gross images of the hearts (top left panel), hematoxylin and eosin staining results (top right panel), and M-mode imaging data (bottom panel) are shown.

(b) Quantifications of the LV internal diameters in end-diastole (LVIDd) and end-systole (LVIDs) and the fractional shortening (FS) and ejection fraction (EF) by echocardiography in rAAV9/shSC or rAAV9/shSUMO1 injected mice (5 × 10¹⁰ vg/mice per each group, n=14 per each group).

(c) Survival of animals following rAAV9-mediated cardiac knockdown of SUMO1.The Kaplan-Meier curves are shown for different doses of rAAV9/ shSUMO1 (n=14 per each group) or rAAV9/shSC (5 × 10¹⁰ vg/mice, n=24).

(d) Representative immunoblot analysis for the indicated cardiac proteins are shown from samples collected 6 weeks after tail-vein injection with rAAV9/shSC (5 × 10¹⁰ vg/mice, n=4) or rAAV9/shSUMO1 (5 × 10¹⁰ vg/mice, n=7) (left panel). Quantification of GAPDH corrected cardiac protein immunoblot signals (right panel).

(e) Ca²⁺-dependence of SERCA2a’s ATPase activity. The ATPase activity was examined in preparations from scramble (●) injected and SUMO1 shRNA () injected hearts (5 × 10¹⁰ vg/mice per each group, n=3 per each group).

All data represent the mean ± the SD. * p < 0.05; ** p < 0.001 vs. the respective control as determined using Student’s t-test. NS: non-significant.

(f) A working model for the regulation of SERCA2a function by SUMOylation. Under basal conditions, SUMOylation enhances SERCA2a’s protein stability and its Ca²⁺ pump function to regulate cardiac contractility. However, increased levels of unSUMOylated SERCA2a due to low SUMO1 protein pools triggers impaired SERCA2a activity and induces cardiac dysfunction under pathophysiological conditions.