Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 279, Issue 6, Pages H3101-H3112Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.2000.279.6.H3101
Keywords
contractility; beta-adrenergic receptor; excitation-contraction coupling; calcium signaling; transgenic; beta-adrenergic receptor kinase
Funding
- NHLBI NIH HHS [HL-61602, HL-61558, HL-36974] Funding Source: Medline
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Heart failure and dilated cardiomyopathy develop in mice that lack the muscle LIM protein (MLP) gene (MLP-/-). The character and extent of the heart failure that occurs in MLP-/- mice were investigated using echocardiography and in vivo pressure-volume (P-V) loop measurements. P-V loop data were obtained with a new method for mice (sonomicrometry) using two pairs of orthogonal piezoelectric crystals implanted in the endocardial wall. Sonomicrometry revealed right-shifted P-V loops in MLP-/- mice, depressed systolic contractility, and additional evidence of heart failure. Cellular changes in MLP-/- mice were examined in isolated single cells using patch-clamp and confocal Ca2+ concentration ([Ca2+]) imaging techniques. This cellular investigation revealed unchanged Ca2+ currents and Ca2+ spark characteristics but decreased intracellular [Ca2+] transients and contractile responses and a defect in excitation-contraction coupling. Normal cellular and whole heart function was restored in MLP-/- mice that express a cardiac-targeted transgene, which blocks the function of beta -adrenergic receptor (beta -AR) kinase-1 (beta ARK1). These data suggest that, despite the persistent stimulus to develop heart failure in MLP-/- mice (i.e., loss of the structural protein MLP), downregulation and desensitization of the beta -ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of bARK1 action may prove an effective therapy for heart failure.
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