Smooth muscle cell-extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy.

Abstract

Vascular spasm is a poorly understood but critical biomedical process because it can acutely reduce blood supply and tissue oxygenation. Cardiomyopathy in mice lacking gamma-sarcoglycan or delta-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.

• Authors: Matthew T Wheeler, Michael J Allikian, Ahlke Heydemann, Michele Hadhazy, Sara Zarnegar, Elizabeth M McNally
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 113 Issue 5 Pg. 668-75 (Mar 2004) ISSN: 0021-9738 [Print] United States
• PMID: 14991064 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytoskeletal Proteins
• DNA, Complementary
• Membrane Glycoproteins
• Sarcoglycans
• Nitric Oxide

Topics

• Alleles
• Animals
• Cardiomyopathies (genetics, pathology)
• Cytoskeletal Proteins (genetics, physiology)
• DNA, Complementary (metabolism)
• Fibrosis
• Genotype
• Immunoblotting
• Membrane Glycoproteins (genetics, physiology)
• Membranes (metabolism)
• Mice
• Mice, Inbred C57BL
• Microcirculation
• Microscopy, Fluorescence
• Models, Anatomic
• Models, Genetic
• Mutation
• Myocardium (cytology, metabolism)
• Myocytes, Cardiac (metabolism)
• Myocytes, Smooth Muscle (pathology)
• Necrosis
• Nitric Oxide (metabolism)
• Permeability
• Sarcoglycans
• Spasm (pathology)
• Transgenes
• Vascular Diseases (metabolism)