DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

Abstract

Background 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. Methodology/Principal Findings 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. Conclusions/Significance 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.

Leptin induces cardiac fibrosis through galectin-3, mTOR and oxidative stress

“…Nonmyocytes from adult male Wistar rats (weighing 250-300 g) were obtained by differential centrifugation of cardiac cells released after retrograde Langendorff perfusion and enzymatic digestion of the hearts, as previously described [23]. Isolated hearts were first perfused for 2-3 min at 368C-378C with a nominally calcium-free Tyrode solution containing 0.2 mmol/l EGTA, and then for approximately 3-4 min with the same Tyrode solution containing 251 UI of collagenase type II (Worthington) and 0.1 mmol/l CaCl 2 .…”

“…Total proteins were prepared as previously described [23] from either cell extracts isolated from cardiac myofibroblasts or cardiac homogenates from obese and control rats. Proteins were separated by SDS-PAGE on 10% polyacrylamide gels and transferred to polyvinylidene difluoride membranes (Hybond-P; Amersham Biosciences, Piscataway, New Jersey, USA).…”

A Novel BioTarget in Treatment of Heart Failure: Changes in Serum Galectin-3 Levels after Spironolactone Therapy

“…Thus, elevated levels of Gal-3 are associated with cardiac fibrosis [6]. It has been demonstrated that GAL-3 expression is stimulated by aldosterone and stimulated GAL-3 plays a critical role in vascular remodelling and inflammation [7]. Use of mineralocorticoid receptor antagonists (MRAs) has provided 35% reductions in hospital admissions due to worsening heart failure by decreasing myocardial and vascular fibrosis [8].…”

Galectin-3 Mediates Aldosterone-Induced Vascular Fibrosis

“…Indeed, it has been recently demonstrated that angiotensin II stimulates Gal-3 expression in cardiac myofibroblasts. 24 Several inhibitors of Gal-3 have been well described, such as lactose, N-Acetyl-D-lactosamine, and the modified citrus pectin (MCP) 25 (a complex water soluble indigestible polysaccharide riche in β-galactose). MCP contains fragments of the original pectin molecule, including rhamnogalacturonan 1 regions which contain galactan side-chains 26 which are recognized CRD of Gal-3 27,28 with a high affinity and block the lectin's activity.…”