Collagen metabolism in cultured adult rat cardiac fibroblasts

Response to angiotensin II and aldosterone

Christian G. Brilla, Guoping Zhou, Luiz Matsubara, Karl Weber

Research output: Contribution to journalArticle

598 Citations (Scopus)

Abstract

Myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). In renovascular hypertension, this presents as a reactive perivascular and interstitial fibrosis in not only the pressure overloaded, hypertrophied left ventricle but also the normotensive, nonhypertrophied right ventricle. It therefore would appear that circulating hormonal and not hemodynamic factors are responsible for this adverse fibrous tissue response. To ascertain whether the RAAS effector hormones angiotensin II (AII) or aldosterone (ALDO) directly stimulate collagen synthesis or inhibit collagenase production we used cell culture. Adult rat cardiac fibroblasts (Fb) were cultured since these cells express mRNA for types I and m collagens, the major fibrillar collagens in the heart, and collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Collagen synthesis, determined by 3H-proline incorporation, and collagenase activity were measured in confluent, quiescent Fb after 24 h incubation with various concentrations of AII or ALDO (10−11−10−6M) in the presence or absence of either 10−5M type 1 (DuP 753) and type 2 (PD 123177) AII or 10−9−3 x 10−6M ALDO (spironolactone) receptor antagonists, respectively Collagen synthesis, normalized per total protein synthesis, increased significantly (P< 0.005) after incubation with either 10−9M ALDO (5.9 ± 1.0%) or 10−7M AII (5.3 ± 1.2%) compared with untreated control cells (2.9 ± 0.5%) of the same passage (p6-p10). This increase in collagen synthesis could be completely abolished by either types 1 or 2 AII receptor antagonists in AII stimulated Fb or the competitive ALDO receptor antagonist, spironolactone, at equimolar concentration in ALDO stimulated Fb. AII significantly decreased collagenase activity which could be completely abolished by PD 123177, but not DuP 753, while ALDO had no effect on collagenase activity. The mineralocorticoid, ALDO, stimulates collagen synthesis in cultured adult rat cardiac Fb in concentrations similar to those found in plasma in renovascular hypertension and this response appears to occur via type I corticoid receptors. AII appears to stimulate collagen synthesis by both type 1 and 2 AII receptors, but only in high concentrations that could be generated locally within the myocardium. In addition, AII unlike ALDO inhibits collagenase activity that could be attenuated only by type 2 receptor blockade. These findings suggest a direct interaction between ALDO, AII and cardiac Fb in mediating myocardial fibrosis in hypertensive heart disease.

Original languageEnglish (US)
Pages (from-to)809-820
Number of pages12
JournalJournal of Molecular and Cellular Cardiology
Volume26
Issue number7
DOIs
StatePublished - Jan 1 1994
Externally publishedYes

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Aldosterone
Angiotensin II
Collagen
Fibroblasts
Collagenases
Mineralocorticoid Receptor Antagonists
Renovascular Hypertension
Fibrosis
Losartan
Renin-Angiotensin System
Heart Ventricles
Angiotensin II Type 2 Receptor Blockers
Angiotensin Type 2 Receptor
Fibrillar Collagens
Angiotensin II Type 1 Receptor Blockers
Mineralocorticoid Receptors
Mineralocorticoids
Angiotensin Type 1 Receptor
Matrix Metalloproteinase 1
Spironolactone

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Collagen metabolism in cultured adult rat cardiac fibroblasts : Response to angiotensin II and aldosterone. / Brilla, Christian G.; Zhou, Guoping; Matsubara, Luiz; Weber, Karl.

In: Journal of Molecular and Cellular Cardiology, Vol. 26, No. 7, 01.01.1994, p. 809-820.

Research output: Contribution to journalArticle

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