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Title: Mechano-sensing in cardiac cells
Author: Hooper, Charlotte
ISNI:       0000 0004 2743 2575
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2012
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The myocardium is exposed to mechanical stress from fluctuations in blood flow and due to active contraction. To maintain function during prolonged increased workload and stress the heart undergoes maladaptive hypertrophy which can progress to heart failure. Cardiac adaptation encompasses many cell signalling pathways which must be intricately regulated. These mechanisms are poorly understood, however mechano-sensors are thought to play an important role. Our aim was to expand understanding of cellular signalling associated with myocardial growth. We hypothesised that mechanical stress, nitric oxide and mechano-sensors participate in cardiac adaptation. To explore this we used an in vitro model of mechanical stress and four animal models of heart failure: aortic banding, myocardial infarction, muscle LIM protein (MLP) knockout and an angiotensin II time-course model. In vitro cardiomyocytes and fibroblasts were cyclically stretched to examine adaptive or maladaptive stress. We examined two potential mechano-sensitive proteins: lipoma preferred partner (LPP) and thyroid receptor interacting protein 6 (TRlP6) upon cardiac adaptation to determine their implication in such mechanisms. Our findings indicate that they are widely expressed in the heart. LPP and TRlP6 increased in all the in vivo models except after MI suggesting their potential involvement in mechano- stress dependent growth. Mechanical stress altered LPP and TRIP subcellular distribution. LPP knockdown led to the accumulation of α-actinin aggregates and increased protein degradation. Stretch upregulated proteins associated with cardiomyocyte growth, which was mimicked by nitric oxide (NO) synthesis inhibition suggesting that stretch-mediated growth may be NO-dependent. NO inhibition altered LPP, TRlP6 and MLP subcellular distribution in a way that promotes hypertrophy and there exists complex interactions between the NOS isoforms to regulate gene expression. NO inhibition also increased CLOCK protein, which regulates circadian-dependent gene expression. Our findings indicate that cardiac adaptation involves a complex interplay between mechanical and neurohumoral cues that induce adaptive or maladaptive growth.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available