P499The triterpenes erythrodiol and uvaol modulate proliferation and fibrosis induced by angiotensin II in cardiac myofibroblats

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The cardiovascular benefits of the Mediterranean diet have been attributed to a high content of monounsaturated fatty acids (oleic acid), as well as to a wide variety of minor components such as the triterpenic acids and the diols, uvaol and erythrodiol. However, the effect of these compounds on cardiac cells, is unknown. We thus proposed to investigate whether erythrodiol and uvaol, might modulate cardiac myofibroblasts in proliferation and collagen production induced by angiotensin II (AII). The possible mechanisms involved in this modulation were also explored.


The proliferative response of cardiac myofibroblats from adult rats (passage 2-3) to AII (10-6M) was studied in the presence or absence of either erythrodiol or uvaol (1-50 µM). The effect of either erythrodiol or uvaol on apoptosis was also assessed by Annexin V binding. The potential roles of Ras/ERK pathway, Jun N terminal Kinase (JNK) and peroxisome proliferator activator receptor-γ (PPAR-γ) in the effect of both triterpenes, on the previous actions were evaluated in the presence of their respective inhibitors: PD 98059 (5-50µM), SP 600125 (5-20 µM) and GW9662 (5-20 µM). Protein levels of collagen I, and galectin 3 in response to of AII in the presence or absence of both triterpnes were studied.


AII induced proliferation of cardiac myofibroblasts in a dose-dependent manner, which was progressively reduced (p < 0.05) in the presence of either erythrodiol or uvaol. ERK 1/2 phosphorylation induced by AII was reduced only in the presence of the highest doses of erythrodiol and uvaol (25-50 µM). Pretreatment with the specific inhibitor of the PPAR-γ (peroxisome proliferator-activated receptor), GW9662, reversed the effect induced by both triterpenes on proliferative effect of AII, while the JNK inhibitor, SP600125, did not modify this effect. Both triterpenes at the dose of 25-50 µM produced an increase in annexing-V binding in the presence or absence of AII. Pretreatment with either SP600125 or GW9662 blocked the apoptotic response induced by triterpenes. The presence of both triterpenes also reduced protein levels of collagen I and galectin 3 induced by aAII.


Erythrodiol and uvaol modulate growth and survival of cardiac myofibroblasts. They inhibit the proliferation induced by AII in a PPAR-γ-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-γ. Both triterpenes modulate the fibrotic response induced by AII by diminishing collagen I and galectin 3 productions.

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