Proteasome inhibition promotes regression of left ventricular hypertrophy

William E. Stansfield, Ru Hang Tang, Nancy C. Moss, Albert S. Baldwin, Monte Willis, Craig H. Selzman

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Current research in left ventricular hypertrophy (LVH) has largely focused on its progression and therapeutic mechanisms to prevent or slow its development. Few studies have centered on the regression or treatment of existing LVH. Nuclear factor-κB (NF-κB) is an inflammatory transcription factor that has been shown to be involved in LVH development. We hypothesized that proteasome-mediated NF-κB inhibition would prevent the development of LVH and promote its regression. A murine model of reversible hypertrophy was employed by administering isoproterenol (Iso) subcutaneously for 7-14 days. The proteasome inhibitor, PS-519, was delivered both concurrently and after Iso treatment. LVH was quantified by heart weight-to-body weight ratios, histology, transthoracic echocardiography, and hypertrophic gene expression. After 7 days of Iso treatment, all measures indicated successful development of LVH. Another group was treated for 7 days and then observed for an additional 7 days. This group experienced normalization of Iso-induced cell size, wall thickness, and β-myosin heavy chain expression. When administered concurrently, PS-519 prevented Iso-induced LVH at 7 days. Furthermore, when PS-519 was given to animals during the second week of continued Iso treatment, these animals also experienced regression of hypertrophy by several measures. The success of proteasome inhibition in preventing LVH development and in promoting LVH regression, even in the face of continued hypertrophic stimulation, demonstrates its potential use as a clinically accessible strategy for treating patients with a variety of LVH-associated cardiomyopathies.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number2
DOIs
StatePublished - Feb 1 2008
Externally publishedYes

Fingerprint

Left Ventricular Hypertrophy
Proteasome Endopeptidase Complex
Isoproterenol
Hypertrophy
Therapeutics
Proteasome Inhibitors
Myosin Heavy Chains
Cardiomyopathies
Cell Size
Cell Wall
Echocardiography
Histology
Transcription Factors
Body Weight
Gene Expression
Weights and Measures

Keywords

  • Isoproterenol
  • Nuclear factor-κB
  • PS-519
  • Regression

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Proteasome inhibition promotes regression of left ventricular hypertrophy. / Stansfield, William E.; Tang, Ru Hang; Moss, Nancy C.; Baldwin, Albert S.; Willis, Monte; Selzman, Craig H.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 2, 01.02.2008.

Research output: Contribution to journalArticle

Stansfield, William E. ; Tang, Ru Hang ; Moss, Nancy C. ; Baldwin, Albert S. ; Willis, Monte ; Selzman, Craig H. / Proteasome inhibition promotes regression of left ventricular hypertrophy. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 294, No. 2.
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