Angiotensin-converting enzyme in systemic sclerosis: from endothelial injury to a genetic polymorphism.
The main pathologic hallmark of systemic sclerosis (SSc) is endothelial derangement; the pathologic alterations of the vessel wall in SSc are strikingly similar to the modification detected in the atherosclerotic lesions, and it is now evident that SSc is also characterized by accelerated macrovascular disease. Peptides related to angiotensin II, the final product of the renin-angiotensin system (RAS), play a role as regulators of endothelial cell function. Angiotensin-converting enzyme (ACE), the key enzyme in the RAS, is the predominant pathway of angiotensin II formation in blood and tissues. In intron 16 of the gene encoding for ACE an insertion/deletion (I/D) polymorphism, consisting of the presence or absence of a 287-base pair Alu sequence, has been identified. This polymorphism has been related to ACE enzyme levels, and data from experimental studies reported a functional role for this polymorphism in modulating the angiotensin II levels. We previously documented a high ACE D allele frequency in SSc patients and its role in increasing the risk of SSc, thus suggesting that the I/D polymorphism might be a useful genetic marker to identify SSc patients at risk to develop a severe vascular disease, frequently leading to gangrene. Moreover, our preliminary data, besides supporting the role of ACE I/D polymorphism as a predisposing factor to SSc, demonstrated its involvement in accelerated macrovascular disease by increasing the intima media thickness. Therefore, in SSc, not only endothelial dysfunction, but also vascular damage, linked to ACE I/D polymorphism, may significantly contribute to accelerated macrovascular disease, as the ACE D allele, by regulating both the production of angiotensin II and the degradation of bradykinin, contributes to mechanisms involved in the induction and maintenance of vessel wall modification.
Guiducci
Serena
S
Division of Medicine I and Rheumatology, Villa Monna Tessa, Viale Pieraccini 18, 50139, Florence, Italy. serena16@libero.it
Fatini
Cinzia
C
Rogai
Veronica
V
Cinelli
Marina
M
Sticchi
Elena
E
Abbate
Rosanna
R
Cerinic
Marco Matucci
MM
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000809:Angiotensins / Q000378:metabolism; D000818:Animals; D004727:Endothelium / Q000187:drug effects / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic / Q000235:genetics*; D012083:Renin / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000809:Angiotensins; D007703:Peptidyl-Dipeptidase A; D012083:Renin