Smooth muscle cell–extrinsic vascular spasm arises from cardiomyocyte degeneration in sarcoglycan-deficient cardiomyopathy
Matthew T. Wheeler, … , Sara Zarnegar, Elizabeth M. McNally
Matthew T. Wheeler, … , Sara Zarnegar, Elizabeth M. McNally
Published March 1, 2004
Citation Information: J Clin Invest. 2004;113(5):668-675. https://doi.org/10.1172/JCI20410.
View: Text | PDF
Article Cardiology

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 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.

Authors

Matthew T. Wheeler, Michael J. Allikian, Ahlke Heydemann, Michele Hadhazy, Sara Zarnegar, Elizabeth M. McNally

×

Figure 1

Options: View larger image (or click on image) Download as PowerPoint
Construction and expression of cardiomyocyte-specific sarcoglycan transg...
Construction and expression of cardiomyocyte-specific sarcoglycan transgenes. (A) Full-length murine γ-sarcoglycan (γ-sg) or δ-sarcoglycan (δ-sg) cDNA was ligated into a vector containing the 5.6-kb murine α-MHC promoter (15) to create MHG or MHD, respectively. Transgenic mice with the MHG transgene were crossed with γ-sarcoglycan–null (gsg–/–) mice to generate gsg–/–/MHG mice. Transgenic mice with the MHD transgene were crossed with δ-sarcoglycan–null (dsg–/–) mice generating dsg–/–/MHD mice. pA, polyadenylation signals. (B) Immunoblot of whole heart extracts from normal, gsg–/–, dsg–/–, gsg–/–/MHG, and dsg–/–/MHD animals at 12 weeks of age using γ-sarcoglycan Ab showed γ-sarcoglycan expression was absent in the hearts of gsg–/– and dsg–/– animals, but was restored in transgenic animals. Quantitative Western blot analysis determined the level of γ-sarcoglycan expression in gsg–/–/MHG animals to be sevenfold above normal. (C) δ-Sarcoglycan expression was restored to normal levels by expression of the MHD transgene in dsg–/–/MHD hearts. Expression of δ-sarcoglycan from the MHD transgene also resulted in recovery of γ-sarcoglycan to normal levels (last lane). (D) Immunoblots for the remaining sarcoglycan subunits showed that α-sarcoglycan (ASG) expression is recovered in hearts with either γ- or δ-sarcoglycan transgene expression. β-Sarcoglycan protein (BSG) is increased to normal levels, and ζ-sarcoglycan protein (ZSG) levels are not significantly different in transgenic hearts. Loading control is shown for B, C, and D. Coom., Coomassie blue.