Studies on vascular remodeling in acute coronary artery disease

Atherosclerosis is an arterial disease, characterized by endothelial dysfunction, vascular inflammation, and lipid accumulation in the vessel wall. Unstable coronary syndroms may be initiated by rupture of the atherosclerotic plaque, which may be caused by activation of matrix metalloproteinases (MMPs), apoptosis and angiogenesis. Saphenous vein grafts are commonly used to bypass atherosclerotic coronary arteries. The long-term patency of vein grafts is low due to vascular remodeling, and MMPs may play a role for this. MMPs are zincdependent endopeptidases, degrading all components of the extracellular matrix. The regulation of MMPs involves transcriptional regulation, cleavage into active enzymes, and inhibition by tissue inhibitors of metalloproteinases (TIMPs).

The aim of this thesis was to compare features of plaques from patients with stable and unstable angina to understand factors underlying plaque instability, and to study possible vein graft remodeling induced by standard surgical preparation. Specific objectives were to compare protease expression, apoptosis and angiogenesis between stable and unstable plaques, to study MMP9 induction in vein grafts after surgical handling, and to explore the impact of cytokines on MMP1 and MMP9 induction in monocytes and macrophages.

Human coronary plaques from patients with stable and unstable angina were obtained through directional coronary atherectomy. The unstable plaques had an increased gene expression of MMP9 and plasminogen activator inhibitor-1, and an increased infiltration of macrophages and Tlymphocytes. Positive immunostaining for MMP9, tissue plasminogen activator, activator protein-1 (AP-1) and nuclear factor kappa B was up-regulated in unstable plaques, while plasma MMP9 antigen increased. Apoptosis and angiogenesis was induced in the plaques from patients with unstable angina.

Human saphenous vein grafts were collected at the start of surgical preparation for coronary artery bypass grafting, and at the time of anastomosis to the heart. MMP9 expression was increased by surgical handling. Patients with stable angina had increased MMP9 gene and protein expression, as well as increased pro and active MMP9 after surgical handling, while unstable patients did not increase in these parameters.

To investigate the impact of cytokines on protease expression in macrophages, we treated differentiated THP1 cells with interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha). MMP 1 and MMP9 were increased by monocyte differentiation. IL-1beta, but not TNF-alpha, further induced MMP9. The differentiation process was associated with an increased binding of AP-1 to the promoter regions of MMP1 and MMP9. c-Jun expression was increased by monocyte differentiation.

Increased MMP9 expression, apoptosis and angiogenesis induction may contribute to plaque destabilization in patients with unstable angina. Surgical handling increased MMP9 in vein grafts, indicating that tender preparation may be beneficial for maintenance of graft patency. The differentiation process appears to be the main regulator of macrophage MMP expression.

List of scientific papers

I. Chen F, Eriksson P, Hansson GK, Herzfeld I, Klein M, Hansson LO, Valen G (2005). Expression of matrix metalloproteinase 9 and its regulators in the unstable coronary atherosclerotic plaque. Int J Mol Med. 15(1): 57-65.
https://pubmed.ncbi.nlm.nih.gov/15583828

II. Chen F, Eriksson P, Kimura T, Herzfeld I, Valen G (2005). Apoptosis and angiogenesis are induced in the unstable coronary atherosclerotic plaque. Coron Artery Dis. 16(3): 191-7.
https://pubmed.ncbi.nlm.nih.gov/15818089

III. Chen F, Eriksson P, Whatling C, Vaage J, Valen G (2005). Surgical handling of saphenous vein grafts induces expression of matrix metalloproteinase 9. [Manuscript]

IV. Chen F, Zhu CY, Hamsten A, Valen G, Eriksson P (2005). Monocyte differentiation is a key regulator of MMP1 and MMP9 expression. [Manuscript]