Reduced cardiac expression of plasminogen activator inhibitor 1 and transforming growth factor  1 in obese Zucker rats by perindopril

Abstract

Objective: To determine whether angiotensin converting enzyme inhibition by perindopril can reduce cardiac transforming growth factor b1 (TGFb1) and plasminogen activator inhibitor 1 (PAI-1) and therefore control collagen accumulation in an animal model with the metabolic syndrome such as the obese Zucker rat (OZR). Animals: Male OZR (group 1, n = 10); OZR treated with perindopril (group 2, n = 10); and lean Zucker rats (group 3, n = 10). Methods: During six months, group 2 received 3 mg/kg/day of perindopril orally and group 1 and group 3 were given a vehicle. Hearts were processed for pathology studies including immunohistochemical analysis with antibodies to PAI-1, TGFb1, collagen type I, and collagen type III. Results: Group 2 had lower blood pressure (126.7 (2) v 148.6 (2.7) mm Hg, p , 0.01) than untreated OZR and had decreased cardiac PAI-1 (3.6 (0.4) v 13.5 (1.7)% of positive area/field, p , 0.01), TGFb1 in myocytes (0.13 (0.1) v 9.14 (4.7)%/area, p , 0.01) and in interstitium (19.8 (6.8) v 178.9 (27.4) positive cells/area, p , 0.01), collagen I (3 (0.8) v 13.3 (1)%/area, p , 0.01), collagen III (5 (0.6) v 9.5 (0.9)%/area, p , 0.01), and collagen I to collagen III ratio (0.59 (0.13) v 1.40 (0.15) p , 0.01) compared with untreated OZR. Conclusion: These results suggest that perindopril reduces cardiac PAI-1 and TGFb1 and ameliorates cardiac fibrosis in a rat model with multiple cardiovascular risk factors.T he association of obesity, non-insulin dependent diabetes mellitus, and arterial hypertension constitutes the well known metabolic syndrome X, which is deeply involved in the development of cardiovascular disease with deleterious consequences.1 In addition, cardiac fibrosis, one of the major factors in the development of heart failure, is highly prevalent in all the aforementioned diseases.Accumulated information supports the notion that angiotensin II has, independently of its hypertensive effect, an essential role in cardiac fibrogenesis by itself and through its action on transforming growth factor b1 (TGFb1) and plasminogen activator inhibitor 1 (PAI-1).2 3 Angiotensin II induces TGFb1, a multifunctional profibrogenic cytokine that regulates cell differentiation of fibroblast into myofibroblast.4 5 Both fibroblast and, especially, myofibroblast regulate fibrogenesis in the heart by producing collagen in the cardiac interstitium. Interestingly, cardiac myofibroblasts express requisite components of the renin-angiotensin system, including angiotensinogen, renin, and angiotensin converting enzyme (ACE), and can generate angiotensin II de novo.6 7 Moreover, angiotensin II can also induce PAI-1, which inhibits activation not only of plasminogen but also of plasmin matrix metalloproteinases (collagenases), which are involved in collagen degradation.8 Consequently, increased PAI-1 concentration either in plasma or in tissue can reduce extracellular matrix degradation, contributes to the accumulation of interstitial collagen, and leads to impaired function of the fibrinolytic system. Therefore, thrombotic e...

Cardiac Remodeling in Obesity

“…Increased fibrosis in coronary vessels as well as accumulation of collagen in the cardiac interstitium was detected in a high-fat diet-induced rabbit model of obesity (39). Leptin signaling may contribute to regulation of cardiac ECM in obesity, since increased fibrosis has been described in the hearts of ob/ob mice (391,392) and in Zucker (fa/fa) rats (350,394). We have recently demonstrated using primary human pediatric ventricular myocytes that leptin increased procollagen type III and type IV mRNA and decreased procollagen type I levels but did not change total collagen synthesis (217).…”

“…Increased interstitial fibrosis has been described in the hearts of Zucker (fa/fa) rats (350,394) and in UCP-DTA mice (54). In ob/ob mice, fibrosis occurs mainly in the coronary perivascular region (391,392).…”

Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities

“…Pharmacologic inhibition studies suggest that AT1 signaling may play an important role in the pathogenesis of obesity-associated cardiac fibrosis. In obese Zucker rats, ACE inhibition with perindopril attenuated myocardial collagen synthesis and reduced PAI-1 and TGF-β levels (79). Moreover, in ob/ob mice treatment with ACE inhibitors or AT1 blockers decreased perivascular coronary fibrosis.…”

Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community

“…33 Increased cardiac type III collagen deposition has also been described in the obese Zucker rat model. 34 Although the underlying mechanisms for increased cardiac collagen deposition in obesity are unclear, it is tempting to speculate that excessive collagen deposition contributes to obesity-related LV hypertrophy. 35 Interestingly, a recent study of obese individuals found that PIIINP levels were independently correlated with indices of insulin resistance, which has also been postulated to play a role in the development of LV hypertrophy.…”