Contribution of caveolin protein abundance to augmented nitric oxide signaling in conscious dogs with pacing-induced heart failure

Joshua M. Hare, Robert A. Lofthouse, George J. Juang, Laurence Colman, Kelly M. Ricker, Benjamin Kim, Hideaki Senzaki, Suyi Cao, Richard S. Tunin, David A. Kass

Research output: Contribution to journalArticle

Abstract

Myocardial NO signaling appears elevated in heart failure (HF). Whether this results from increased NO production, induction of the high-output NO synthase (NOS)2 isoform, or changes in NOS regulatory pathways (such as caveolae) remains controversial. We tested the hypothesis that increased abundance of caveolin-3 and/or sarcolemmal caveolae contribute to increased NO signaling in pacing-induced HF. Abundance of caveolin-3 (0.59 ± 0.08 versus 0.29 ± 0.08 arbitrary units, P = 0.01) but not caveolin-1 was increased in HF compared with control conditions, assessed by Western blot. Additionally, transmission electron microscopy revealed increased caveolae (2.7 ± 0.4 versus 1.3 ± 0.3 per micrometer myocyte membrane, P<0.005). The association between caveolin-3 and NOS3 at the sarcolemma and T tubules was unchanged in HF compared with control myocytes. The impact of NOS inhibition with L-N(G)-methylarginine hydrochloride (L-NMMA) on β-adrenergic inotropy was assessed in conscious dogs before and after HF. In control dogs, dobutamine (5 μg · kg-1 · min-1) increased +dP/dt by 36 ± 7%, and this was augmented to 66 ± 24% by 20 mg/kg L-NMMA (P = 0.04 versus without L-NMMA, n = 8) but not affected by 10 mg/kg L-NMMA (34 ± 10%, P = NS; n = 8). In HF, dobutamine +dP/dt response was depressed (P<0.001 versus control), and increased concentrations were required to match control inotropic responses (10 to 15 μg · kg-1 · min-1, 48 ± 7%). L-NMMA enhanced +dP/dt responses similarly at 10 mg/kg (61 ± 17%, P = 0.02; n = 4) and 20 mg/kg (54 ± 7%, P = 0.04; n = 7). Caveolin-3 abundance positively correlated with L-NMMA augmentation of dobutamine inotropic responses in HF (r = 0.9, P = 0.03; n = 4). Thus, in canine pacing-induced HF, expression of caveolin-3 and of sarcolemmal caveolae is increased. This increase is associated with augmented agonist-stimulated NO signaling, likely via a compartmentation effect.

Original languageEnglish (US)
Pages (from-to)1085-1092
Number of pages8
JournalCirculation research
Volume86
Issue number10
DOIs
StatePublished - May 26 2000

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Keywords

  • Caveolae
  • Compartmentation
  • Heart failure
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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