Cellular and molecular mechanisms of coronary artery spasm: Lessons from animal models

Hiroaki Shimokawa

Research output: Contribution to journalArticlepeer-review

149 Citations (Scopus)

Abstract

Coronary artery spasm plays an important role in the pathogenesis of a wide variety of ischemic heart diseases, especially in the Japanese population. Because coronary artery spasm can be induced by a variety of stimuli with different mechanisms of action, the occurrence of the spasm appears to be due to the local hyperreactivity of the coronary artery rather than to an enhanced stimulation with a single mechanism of action. Several lines of evidence indicate that coronary artery spasm is caused primarily by smooth muscle hypercontraction whereas the contribution of endothelial dysfunction may be minimal. In order to elucidate the cellular and molecular mechanisms of the spasm, porcine models of the spasm were developed. In the first model with balloon injury and high-cholesterol feeding, a close topological correlation between the early atherosclerotic lesions and the spastic sites was noted, whereas in the second model with an inflammatory cytokine the potential importance of coronary inflammatory changes, especially at the adventitia, was noted. Subsequent studies in vivo and in vitro demonstrated that protein kinase C (PKC) and Rho-kinase are substantially involved in the intracellular mechanism of the spasm, resulting in increases in the mono- and diphosphorylations of myosin light chain (MLC). Furthermore, molecular biological analyses demonstrated that Rho-kinase is upregulated at the spastic site (at all levels, including mRNA, protein, and activity), resulting in the inhibition of MLC phosphatase through the phosphorylation of its myosin binding subunit and thereby causing the increase in MLC phosphorylations. Preliminary results also suggest that the long-term inhibition of Rho-kinase is effective in inhibiting the development of arteriosclerotic vascular lesions in several porcine models. Thus, Rho- kinase could be regarded as a novel therapeutic target for coronary arteriosclerosis in general and coronary artery spasm in particular.

Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalJAPANESE CIRCULATION JOURNAL
Volume64
Issue number1
DOIs
Publication statusPublished - 2000 Jan

Keywords

  • Coronary artery spasm
  • Myosin light chain
  • Myosin phosphatase
  • Protein kinase C
  • Rho-kinase
  • Vascular smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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