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INCREASED PASSIVE AND CONTRACTILE STRESS WITHIN THE MYOFILAMENTS CONTRIBUTE TO THE LOSS OF MECHANOSENSING IN THE HEART DURING THE PROGRESSION TO HEART FAILURE
  1. A Paudyal1,
  2. S Dewan2,
  3. P De Tombe2,
  4. S Boateng1
  1. 1University of Reading, Institute for Cardiovascular & Metabolic Research
  2. 2Loyola University, Cell and Molecular Physiology

Abstract

Mechanosensing in the heart is an essential process allowing it to adapt to changes in the passive forces generated by changes in blood, and the forces produced by crossbridge cycling. We hypothesized that different mechanosensors may respond differently to these forces.

We examined a guinea pig model of angiotensin II infusion (400ng/kg/min) spanning from early hypertrophy to heart failure. Using Western blotting, we show that desmin was upregulated during heart failure by 55% (n=7, P=0.03), while a second mechanosensor protein, Muscle LIM Protein (MLP) was found to have increased cytoplasmic to nuclear ratio by 88% (n=4, P=0.009) during compensatory hypertrophy, while this ratio decreased significantly during heart failure.

We uncoupled the two sources of mechanical stress using cultured neonatal rat myocytes. To mimic passive stretch, we exposed myocytes to 48 hours of cyclic mechanical stretch at 1Hz, and to mimic the crossbridge cycling force, we electrically paced myocytes at 6.8 V (1Hz) for 48 hours. Results show that levels of desmin increased 23% (n=5, P=0.02) only in response to passive stretch. In contrast, the ratio of cytoplasmic to nuclear MLP decreased 50% (n=4, p=0.02) only in response to pacing.

We inhibited crossbridge cycling by treating myocytes with blebbistatin (10 µM). This resulted in a ∼3 fold increase in the cytoplasmic to nuclear MLP ratio (n=8, p=0.02), while the desmin level remained unchanged. These data suggest that the failing heart may experience a prolonged increase in passive stretch and increased mechanical stress within the sarcomeres leading to a progressive loss of mechanosensing.

  • CARDIAC PROCEDURES AND THERAPY

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