Cellular and functional defects in a mouse model of heart failure

Giovanni Esposito, Luis Fernando Santana, Keith Dilly, Jader Dos Santos Cruz, Lan Mao, W. J. Lederer, Howard A. Rockman

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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 β-adrenergic receptor (β-AR) kinase-1 (βARK1). 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 β-ARs may play a pivotal role in the pathogenesis. Furthermore, this work suggests that the inhibition of βARK1 action may prove an effective therapy for heart failure.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number6 48-6
StatePublished - 2000
Externally publishedYes


  • β-Adrenergic receptor
  • β-Adrenergic receptor kinase
  • Calcium signaling
  • Contractility
  • Excitation-contraction coupling
  • Transgenic

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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