Increased Myocardial Collagen Content in Transgenic Rats Overexpressing Cardiac Angiotensin-Converting Enzyme Is Related to Enhanced Breakdown of N -Acetyl-Ser-Asp-Lys-Pro and Increased Phosphorylation of Smad2/3

Abstract

Background-Although increased activity of angiotensin-converting enzyme (ACE) has been associated with increased cardiac collagen, no studies to date have established a direct cause-and-effect relation between the two. Methods and Results-We used transgenic rats that overexpress human ACE selectively in the myocardium. Two independent heterozygous transgenic rat lines were studied, one expressing 2 to 3 copies (L1172) and the other expressing 5 to 10 copies (L1173) of the ACE transgene. These rats were normotensive but developed a proportionate increase in myocardial collagen depending on the ACE gene dose (up to 2.5-fold, PϽ0.01), but cardiac angiotensin II levels remained normal, whereas collagen content reversed to control levels on ACE inhibition. To explain these changes, we investigated N-acetyl-Ser-Asp-Lys-Pro (AcSDKP), an alternative substrate that is catabolized exclusively by ACE. Increased cardiac expression of ACE was paralleled by a reciprocal decrease in cardiac AcSDKP and a proportionate increase in phosphorylated Smad2 and Smad3, all of which normalized after both ACE inhibition and AcSDKP infusion. Furthermore, a functional link of this signaling cascade was demonstrated, because AcSDKP inhibited Smad3 phosphorylation in a dose-dependent manner in cultured cardiac fibroblasts and in vivo. Conclusions-Our findings suggest that increased cardiac ACE activity can increase cardiac collagen content by degradation of AcSDKP, an inhibitor of the phosphorylation of transforming growth factor-␤ signaling molecules Smad2 and Smad3. This implies that the antifibrotic effects of ACE inhibitors are mediated in part by increasing cardiac AcSDKP, with subsequent inhibition of Smad 2/3 phosphorylation.

ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation

“…69 Other triggers of fibrosis include inflammation 70 as seen in cardiac sarcoidosis 71 and autoimmune disorders. 72 In one study, histological changes consistent with myocarditis were reported in 66% of atrial biopsy specimens from patients with lone AF, 62 but it is uncertain whether these inflammatory changes were a cause or consequence of AF.…”

Decreased Endogenous Levels of Ac-SDKP Promote Organ Fibrosis

“…This hypothesis has been also suggested by Pokharel et al, who recently showed that enhanced breakdown of endogenous Ac-SDKP attributable to cardiac ACE overexpression (because Ac-SDKP is a natural ACE substrate 28 ) is responsible for the increase in cardiac collagen. 29 One interesting finding was that interstitial collagen fraction was not increased with POPi alone, in contrast to PVF; however, the combined treatment of POPi plus Ang II significantly increased interstitial collagen fraction compared with Ang II alone, and this was accompanied by an increase in interstitial cell proliferation and prolyl 4-hydroxylase-expressing cells. These observations may suggest that Ac-SDKP participates in maintenance of the collagen balance, so that a decrease in endogenous levels would affect remodeling of the myocardium similarly to hypertension, which occurs initially in the perivascular portion and progressively extends to cause widespread interstitial fibrosis; this process may be accelerated in the presence of a profibrotic stimulus, such as Ang II.…”

N-acetyl-seryl-aspartyl-lysyl-proline prevents cardiac remodeling and dysfunction induced by galectin-3, a mammalian adhesion/growth-regulatory lectin

“…In fact, Ac-SDKP mediates the anti-inflammatory and antifibrotic effects of ACE inhibitors (22,24). Rats overexpressing cardiac ACE have decreased Ac-SDKP concentration and increased fibrosis in the heart (26). Also, inhibition of Ac-SDKP release from thymosin-␤4 promotes cardiac and renal perivascular fibrosis (PVF) and nephrosclerosis (7).…”