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Vascular spasm is a poorly understood phenomenon
with considerable pathologic implications. In our laboratory, we discovered two different mechanisms
of vascular spasm that affect the coronary arteries. In the first model, we found that a targeted
disruption of the SUR2 genes lead to vascular spasm and cardiac
arrhythmias. In this case, SUR2
null mice developed repeated vascular spasm accompanied by changes on the
surface electrocardiogram. Using
the calcium channel antagonist, we were able to successfully reduce coronary
artery vasospasm. Mice with mutant SUR2 serve as a model for Prinzmetal
variant angina. The SUR2 gene
encodes a protein that binds sulfonylurea agents. These agents are commonly
used to treat diabetes. Our work suggests a mechanism for enhanced
cardiovascular morbidity from the use of sulfonylurea agents.
The
second mechanism of vascular spasm arises from defects extrinsic to vascular
smooth muscle. Mice mutant for
the sarcoglycan components develop focal degeneration throughout their
hearts. It has been suggested
that these focal defects arise from vascular spasm. We found that vascular spasm occurs in mice lacking
sarcoglycan, but that this spasm arises from a vascular smooth muscle cell
extrinsic mechanism. Transgenic
restoration of the cardiomyocyte sarcoglycan complex in sarcoglycan null mice
corrects vascular spasm.
References:
Chutkow,
W. A., J. L. Pu, M. T. Wheeler, J. C. Makielski, C. F. Burant and E. M.
McNally. Prinzmetal like
vasospasm, hypertension and early death result from mutant Sur2 KATP
channels in mice. (2002) J. Clin. Invest. 110: 203-208.
Wheeler,
M.T., M.J. Allikian, A. Heydeman, M. Hadhazy, S. Zarnegar and E. M.
McNally. Smooth muscle cell
extrinsic vascular spasm arises from cardiomyocyte degeneration in
sarcoglycan mutant cardiomyopathy.
J Clin Invest. (2004) 113:668-75.
Wheeler,
M. T., C. E. Korcarz, K. A. Collins, K. A. Lapidos, A. A. Hack, M. R Lyons,
S. Zarnegar, J. U. Earley, R. M. Lang and E. M. McNally. Prevention of secondary vasospasm
limits cardiomyopathy progression. (2004) Am. J. Pathol. 164:1063-71.
Heydemann,
A., Huber, J. M., Kakkar, R., Wheeler, M. T., and McNally, E. M. Functional
nitric oxide synthase mislocalization in cardiomyopathy. J Mol Cell Cardiol
2004; 36:213-223.
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