DIOL triterpenes block profibrotic effects of angiotensin II and protect from cardiac hypertrophy

• Published in: PloS one Vol. 7; no. 7; p. e41545
• Main Authors: Martín, Ruben, Miana, Maria, Jurado-López, Raquel, Martínez-Martínez, Ernesto, Gómez-Hurtado, Nieves, Delgado, Carmen, Bartolomé, Maria Visitación, San Román, José Alberto, Cordova, Claudia, Lahera, Vicente, Nieto, Maria Luisa, Cachofeiro, Victoria
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23-07-2012; Public Library of Science (PLoS)
• Subjects: Angiotensin; Angiotensin II; Angiotensin II - pharmacology; Angiotensins; Animals; Apoptosis; Apoptosis - drug effects; Biology; Brain; Brain natriuretic peptide; Cardiomegaly - chemically induced; Cardiomegaly - metabolism; Cardiomegaly - pathology; Cardiomegaly - prevention & control; Cardiomyopathy; Cell death; Cell Proliferation - drug effects; Chemistry; Collagen; Collagen (type I); Collagen - metabolism; Diabetes; Dose-Response Relationship, Drug; Extracellular matrix; Fibroblasts; Fibrosis; Glycols (Class of compounds); Growth factors; Heart; Heart diseases; Heart failure; Heart hypertrophy; Hypertension; Hypertrophy; Inflammation; Ischemia; JNK protein; Localization; Male; Medicine; Mice; Myofibroblasts - drug effects; Myofibroblasts - metabolism; Myofibroblasts - pathology; Natriuretic peptides; Nitric oxide; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Peroxisome proliferator-activated receptors; Rats; Rodents; Saponins; Terpenes; Triterpenes; Triterpenes - pharmacology; Ventricle; Ventricles (cerebral); Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0041545

The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied.
The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals.
Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac myofibroblasts. They inhibit the angiotensin II-induced proliferation 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.