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Matthew T. Wheeler, Michael J. Allikian, Ahlke Heydemann, Michele Hadhazy, Sara Zarnegar, Elizabeth M. McNally
J Clin Invest. 2004;
113(5):668
doi:10.1172/JCI20410
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V
ascular spasm is a poorly understood but critical biomedical process because it
can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice
lacking γ-sarcoglycan or δ-sarcoglycan is characterized
by focal damage. In the heart, sarcoglycan gene mutations produce regional
defects in membrane permeability and focal degeneration, and it was hypothesized
that vascular spasm was responsible for this focal necrosis. Supporting this
notion, vascular spasm was noted in coronary arteries, and disruption of the
sarcoglycan complex was observed in vascular smooth muscle providing a molecular
mechanism for spasm. Using a transgene rescue strategy in the background of
sarcoglycan-null mice, we replaced cardiomyocyte sarcoglycan expression.
Cardiomyocyte-specific sarcoglycan expression was sufficient to correct cardiac
focal degeneration. Intriguingly, successful restoration of the cardiomyocyte
sarcoglycan complex also eliminated coronary artery vascular spasm, while
restoration of smooth muscle sarcoglycan in the background of sarcoglycan-null
alleles did not. This mechanism, whereby tissue damage leads to vascular spasm,
can be partially corrected by NO synthase inhibitors. Therefore, we propose that
cytokine release from damaged cardiomyocytes can feed back to produce vascular
spasm. Moreover, vascular spasm feeds forward to produce additional cardiac
damage.
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