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Ann Thorac Surg 2004;78:2110-2111
© 2004 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

INVITED COMMENTARY

Division of Cardiothoracic Surgery, Medical University of South Carolina, Strom Thurmond Research Bldg, 770 MUSC Complex, Rm 625, 114 Doughty St, Charleston, SC 29425, USA

Thoracic aortic aneurysms (TAAs) and dissections represent significant clinical challenges to the cardiothoracic surgeon and are associated with a high incidence of perioperative morbidity. Thus, identifying the cellular and molecular mechanisms that drive the formation and progression of these processes holds great clinical relevance. To date, most of our knowledge of the pathobiology has not been a product of direct study, but rather an extension of studies regarding abdominal aortic aneurysms. Hence, the study undertaken by Koullias and colleagues in this issue of The Annals is significant in that studies were performed in aortic tissue samples collected from patients with TAAs and dissections.

A generalized feature of aneurysm development is that significant remodeling of the vascular wall occurs and is characterized by degeneration of the aortic medial layer and degradation of extracellular matrix (ECM). Important ECM proteins that provide support and distensibility to the aortic wall include elastin, collagens and glycoproteins. A family of proteolytic enzymes responsible for ECM degradation are the matrix metalloproteinases (MMPs). A cause-effect relationship has been demonstrated between increased MMP activity to that of ECM degradation and pathologic tissue remodeling. However, there are more than 25 known MMP types, and those directly causative to vascular remodeling, particularly to aneurysmal formation, remain an area of active investigation. While MMP activity is tightly controlled by transcriptional and posttranscriptional mechanisms, an important control point is the synthesis of the endogenous inhibitors, the tissue inhibitors of MMPs (TIMPs). The tissue inhibitors of MMP bind to active MMPs in a 1:1 stoichiometric ratio, and an imbalance in the relative amount of TIMP can in turn directly influence the proteolytic activity of MMPs and thereby ECM turnover. Based on this background, it would seem intuitive to put forth the hypothesis that, in TAAs, abnormal expression of certain MMPs and TIMPs occur that would favor ECM proteolysis and TAA progression. While descriptive in nature, the study by Koullias and associates provides new information that supports this hypothesis.

Abnormal induction and prolonged expression of certain MMP types has been demonstrated in animal models of aortic aneurysms [1, 2], and clinical studies utilizing a nonselective MMP inhibitor in patients with abdominal aortic aneurysms is under way [3, 4]. However, broad-spectrum MMP inhibition can be associated with systemic side effects, and therefore more targeted and specific strategies for interrupting MMP activation in the context of aneurysmal progression is necessary. Past studies utilizing resected specimens taken from patients with abdominal aneurysms have identified increased levels of specific MMP types such as MMP-9 and MMP-2 [5, 6]. The emergence of MMP-9 within the aneurysmal tissue is likely due to an inflammatory response, since this MMP type is strongly localized to neutrophils and macrophages. Indeed, the study by Koullias and colleagues demonstrated through a quantitative histochemical approach an increase in MMP-9 within TAAs that was associated with sites of increased inflammatory cell density. Moreover, these investigators reported that relative levels of MMP-9 were highest in patients with aortic dissections. The relative roles of MMPs and TIMPs either in initiating the intimal tears required for acute aortic dissection or in the progression of pseudoaneurysm formation in chronic dissections are not known at present and were not considered in this study, even though both patient subgroups were included. That represents an interesting avenue of future study as these two processes are likely distinctly different at the molecular level.

Animal studies utilizing pharmacogenetic approaches have demonstrated a causal role for MMP-9 in abdominal aneurysm progression [1, 2]. Thus, while the clinical observations made by Koullias and colleagues are associative, it does strengthen the postulate that increased expression and activation of MMP-9 contributes to the severity of the pathologic remodeling that occurs in TAAs. In this study, the relative ratio of MMP-9 to TIMP-1 was reduced, indicating that the balance between MMP activation and inhibition was altered in favor of a persistent ECM proteolysis. In addition, the abnormality in this MMP-TIMP stoichiometry was further pronounced in aortic dissections. The approach taken by Koullias and colleagues for measuring MMP and TIMP levels was a quantitative histochemical approach and allowed for spatial localization of these proteins within the aneurysmal wall. This study examined a limited number of MMPs, however, and the actual MMP activity within these TAA samples remains to be established. Nevertheless, this study provides compelling evidence that an imbalance between ECM protease activity occurs in TAAs and dissections and likely contributes to the progression of these devastating vascular diseases. Future studies that more carefully profile ECM proteases such as the MMPs and define the mechanistic relationships between alterations in MMP expression and thoracic aortic disease will likely yield novel diagnostic and prognostic insights as well as identify potential therapeutic targets.

	References

Top References

 

1. Pyo R, Lee JK, Shipley JM, et al. Targeted gene disruption of matrix metalloproteinase-9 (gelatinase B) suppresses development of experimental abdominal aortic aneurysms J Clin Invest 2000;105:1641-1649.[Medline]
2. Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms J Clin Invest 2002;110:625-632.[Medline]
3. Thompson RW, Baxter BT. MMP inhibition in abdominal aortic aneurysms. Rationale for a prospective randomized clinical trial Ann NY Acad Sci 1999;878:159-178.[Medline]
4. Curci JA, Mao D, Bohner DG, et al. Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms J Vasc Surg 2000;31:325-342.[Medline]
5. Sakalihasan N, Delvenne P, Nusgens BV, Limet R, Lapiere CM. Activated forms of MMP2 and MMP9 in abdominal aortic aneurysms J Vasc Surg 1996;24:127-133.[Medline]
6. McMillan WD, Pearce WH. Increased plasma levels of metalloproteinase-9 are associated with abdominal aortic aneurysms J Vasc Surg 1999;29:122-127.[Medline]

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