Reduced Cardiac Expression of Plasminogen Activator Inhibitor 1 and Transforming Growth Factor Beta1 in Obese Zucker Rats by Perindopril

Overview

Journal Heart

Date 2004 Dec 18

PMID 15604340

Citations 20

Authors

J E Toblli

G Cao

G Derosa

P Forcada

Affiliations

Soon will be listed here.

Abstract

Objective: To determine whether angiotensin converting enzyme inhibition by perindopril can reduce cardiac transforming growth factor beta1 (TGFbeta1) 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, TGFbeta1, 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), TGFbeta1 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 TGFbeta1 and ameliorates cardiac fibrosis in a rat model with multiple cardiovascular risk factors.

Citing Articles

Advances of research in diabetic cardiomyopathy: diagnosis and the emerging application of sequencing.

He Q, Lai Z, Zhai Z, Zou B, Shi Y, Feng C Front Cardiovasc Med. 2025; 11:1501735.

PMID: 39872882 PMC: 11769946. DOI: 10.3389/fcvm.2024.1501735.

Update on clinical and experimental management of diabetic cardiomyopathy: addressing current and future therapy.

Galis P, Bartosova L, Farkasova V, Bartekova M, Ferenczyova K, Rajtik T Front Endocrinol (Lausanne). 2024; 15:1451100.

PMID: 39140033 PMC: 11319149. DOI: 10.3389/fendo.2024.1451100.

Diabetic cardiomyopathy: Early diagnostic biomarkers, pathogenetic mechanisms, and therapeutic interventions.

Huo J, Feng Q, Pan S, Fu W, Liu Z, Liu Z Cell Death Discov. 2023; 9(1):256.

PMID: 37479697 PMC: 10362058. DOI: 10.1038/s41420-023-01553-4.

Extracellular matrix remodelling in obesity and metabolic disorders.

Musale V, Wasserman D, Kang L Life Metab. 2023; 2(4.

PMID: 37383542 PMC: 10299575. DOI: 10.1093/lifemeta/load021.

The Role of Cardiac Fibrosis in Diabetic Cardiomyopathy: From Pathophysiology to Clinical Diagnostic Tools.

Pan K, Hsu Y, Chang S, Chung C, Lin C Int J Mol Sci. 2023; 24(10).

PMID: 37239956 PMC: 10218088. DOI: 10.3390/ijms24108604.

References

Higashiura K, Ura N, Takada T, Li Y, Torii T, Togashi N . The effects of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist on insulin resistance in fructose-fed rats. Am J Hypertens. 2000; 13(3):290-7. DOI: 10.1016/s0895-7061(99)00174-0. View

Kawano H, Do Y, Kawano Y, Starnes V, Barr M, Law R . Angiotensin II has multiple profibrotic effects in human cardiac fibroblasts. Circulation. 2000; 101(10):1130-7. DOI: 10.1161/01.cir.101.10.1130. View

Nakamura S, Nakamura I, Ma L, Vaughan D, Fogo A . Plasminogen activator inhibitor-1 expression is regulated by the angiotensin type 1 receptor in vivo. Kidney Int. 2000; 58(1):251-9. DOI: 10.1046/j.1523-1755.2000.00160.x. View

Brilla C, Funck R, Rupp H . Lisinopril-mediated regression of myocardial fibrosis in patients with hypertensive heart disease. Circulation. 2000; 102(12):1388-93. DOI: 10.1161/01.cir.102.12.1388. View

Samad F, Pandey M, Bell P, Loskutoff D . Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes. Mol Med. 2000; 6(8):680-92. PMC: 1949975. View

Han D, Isono M, Chen S, Casaretto A, Hong S, Wolf G . Leptin stimulates type I collagen production in db/db mesangial cells: glucose uptake and TGF-beta type II receptor expression. Kidney Int. 2001; 59(4):1315-23. DOI: 10.1046/j.1523-1755.2001.0590041315.x. View

Yevdokimova N, Wahab N, Mason R . Thrombospondin-1 is the key activator of TGF-beta1 in human mesangial cells exposed to high glucose. J Am Soc Nephrol. 2001; 12(4):703-712. DOI: 10.1681/ASN.V124703. View

He J, Ogden L, Bazzano L, Vupputuri S, Loria C, Whelton P . Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med. 2001; 161(7):996-1002. DOI: 10.1001/archinte.161.7.996. View

Zaman A, Fujii S, Sawa H, Goto D, Ishimori N, Watano K . Angiotensin-converting enzyme inhibition attenuates hypofibrinolysis and reduces cardiac perivascular fibrosis in genetically obese diabetic mice. Circulation. 2001; 103(25):3123-8. DOI: 10.1161/01.cir.103.25.3123. View

10.

Huisamen B, Van Zyl M, Keyser A, Lochner A . The effects of insulin and beta-adrenergic stimulation on glucose transport, glut 4 and PKB activation in the myocardium of lean and obese non-insulin dependent diabetes mellitus rats. Mol Cell Biochem. 2001; 223(1-2):15-25. DOI: 10.1023/a:1017528402205. View

11.

de Cavanagh E, Inserra F, Toblli J, Stella I, Fraga C, Ferder L . Enalapril attenuates oxidative stress in diabetic rats. Hypertension. 2001; 38(5):1130-6. DOI: 10.1161/hy1101.092845. View

12.

Amann K, Simonaviciene A, Medwedewa T, Koch A, Orth S, Gross M . Blood pressure-independent additive effects of pharmacologic blockade of the renin-angiotensin and endothelin systems on progression in a low-renin model of renal damage. J Am Soc Nephrol. 2001; 12(12):2572-2584. DOI: 10.1681/ASN.V12122572. View

13.

Petrov V, Fagard R, Lijnen P . Stimulation of collagen production by transforming growth factor-beta1 during differentiation of cardiac fibroblasts to myofibroblasts. Hypertension. 2002; 39(2):258-63. DOI: 10.1161/hy0202.103268. View

14.

Onodera T, Okazaki F, Miyazaki H, Minami S, Ito T, Seki S . Perindopril reverses myocyte remodeling in the hypertensive heart. Hypertens Res. 2002; 25(1):85-90. DOI: 10.1291/hypres.25.85. View

15.

Srikumar N, Brown N, Hopkins P, Jeunemaitre X, Hunt S, Vaughan D . PAI-1 in human hypertension: relation to hypertensive groups. Am J Hypertens. 2002; 15(8):683-90. DOI: 10.1016/s0895-7061(02)02952-7. View

16.

Pannacciulli N, De Mitrio V, Marino R, Giorgino R, De Pergola G . Effect of glucose tolerance status on PAI-1 plasma levels in overweight and obese subjects. Obes Res. 2002; 10(8):717-25. DOI: 10.1038/oby.2002.98. View

17.

Way K, Isshiki K, Suzuma K, Yokota T, Zvagelsky D, Schoen F . Expression of connective tissue growth factor is increased in injured myocardium associated with protein kinase C beta2 activation and diabetes. Diabetes. 2002; 51(9):2709-18. DOI: 10.2337/diabetes.51.9.2709. View

18.

Bertram D, Sassard J, Lo M . Differential evolution of blood pressure and renal lesions after RAS blockade in Lyon hypertensive rats. Am J Physiol Regul Integr Comp Physiol. 2002; 283(5):R1041-5. DOI: 10.1152/ajpregu.00620.2001. View

19.

Suzuki M, Akimoto K, Hattori Y . Glucose upregulates plasminogen activator inhibitor-1 gene expression in vascular smooth muscle cells. Life Sci. 2002; 72(1):59-66. DOI: 10.1016/s0024-3205(02)02182-3. View

20.

Brown N, Kumar S, Painter C, Vaughan D . ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. Hypertension. 2002; 40(6):859-65. DOI: 10.1161/01.hyp.0000040264.15961.48. View