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(Circulation Research. 2001;89:422.)
© 2001 American Heart Association, Inc.

Integrative Physiology

Transgenic Expression of Sarcoplasmic Reticulum Ca²⁺ ATPase Modifies the Transition From Hypertrophy to Early Heart Failure

Kenta Ito, Xinhua Yan, Xin Feng, Warren J. Manning, Wolfgang H. Dillmann, Beverly H. Lorell

From the Department of Medicine (K.I., X.Y., X.F., W.J.M., B.H.L.), Beth Israel Deaconess Medical Center, and Harvard Medical School, Boston, Mass, and Department of Medicine (W.H.D.), University of California–San Diego, La Jolla, Calif.

Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail blorell{at}caregroup.harvard.edu

To examine the contribution of sarcoplasmic reticulum Ca²⁺ ATPase (SERCA2a) to early heart failure, we subjected transgenic (TG) mice expressing SERCA2a gene and wild-type (WT) mice to aortic stenosis (AS) for 7 weeks. At an early stage of hypertrophy (4-week AS), in vivo hemodynamic and echocardiographic indices were similar in TG and WT mice. By 7 weeks of AS, which is the stage of early failure in this model, TG mice with AS had lower mortality than WT mice with AS (6.7% versus 29%). The magnitude of left ventricular (LV) hypertrophy was similar in WT and TG 7-week AS mice. In vivo LV systolic function was higher in TG than in WT 7-week AS mice. In LV myocytes loaded with fluo-3, fractional cell shortening and the amplitude of the [Ca²⁺]_i transients were higher in TG than in WT 7-week AS mice under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca²⁺]_o, 25°C). The rates of relengthening and decay in [Ca²⁺]_i were faster in TG than in WT 7-week AS myocytes. In myocytes from WT 7-week AS compared with sham-operated WT mice, contractile reserve in response to rapid pacing was depressed with impaired augmentation of both peak-systolic [Ca²⁺]_i and the SR Ca²⁺ load. In contrast, contractile reserve and the capacity to augment SR Ca²⁺ load were maintained in TG 7-week AS mice. SERCA2a protein levels were depressed in WT 7-week AS mice, but were preserved in TG 7-week AS mice. These data suggest that defective SR Ca²⁺ loading contributes to the onset of contractile failure in animals with chronic pressure overload.

Key Words: hypertrophy • heart failure • contractile function • mouse myocytes • sarcoplasmic reticulum Ca²⁺ ATPase

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