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Angiotensin converting enzyme II (ACE2) is a component of the renin-angiotensin system (RAS) that negatively regulates angiotensin II (Ang II). Ang II, in turn, affects the expression of matrix metalloproteinases (MMPs) to induce heart remodeling. The specific mechanisms by which ACE2 regulates MMP-2, however, remain unclear. The aim of this study was to investigate the regulatory relationships between Ang II, ACE2, and MMP-2. ACE2 expression was upregulated and downregulated in human cardiofibroblasts (HCFs) by lentiviral infection. Effects on MMP-2 activity, shed ACE2 activity, extracellular signalregulated kinase (ERK) signaling pathway, and ADAM metallopeptidase domain 17 (ADAM17) expression were assessed. ACE2 increased MMP-2 activity, and Ang II inhibited this effect through the Ang II type-1 receptor (AT1R) and ERK1/2 signaling pathway. Ang II also reduced the effect of ACE2 on ERK1/2 levels, the activity of shed ACE2, and adam17 expression in HCFs. Additionally, these Ang II-mediated reductions could be attenuated by AT1R antagonist valsartan. In conclusion, these data help to clarify how ACE2 and Ang II interact to regulate MMP-2 and control tissue remodeling in heart disease. Key words: angiotensin II, angiotensin-converting enzyme II, matrix metalloproteinases-2, human cardiofibroblasts. L'enzyme de conversion de l'angiotensine II (ECA2) est une composante du systeme renine-angiotensine (SRA) qui regule negativement l'angiotensine II (Ang II). L'Ang II, elle, affecte l'expression des metalloproteases de la matrice (MMP) pour induire un remodelage cardiaque. Les mecanismes specifiques par lesquels l'ECA2 regule la MMP-2 demeurent cependant flous. Le but de cette etude etait d'examiner les relations regulatrices entre l'Ang II, l'ECA2 et la MMP-2. L'expression d'ECA2 a ete regulee a la hausse ou a la baisse par une infection lentivirale chez les fibroblastes cardiaques humains (FCH). Les effets sur l'activite de MMP-2, l'activite proteolytique d'ECA2, la voie signaletique de la kinase ERK et l'expression de ADAM17 ont ete evalues. L'ECA2 stimulait l'activite de la MMP-2, et l'Ang II inhibait cet effet par l'intermediaire du recepteur de l'Ang II de type 1 (AT1R) et de la voie signaletique de ERK1/2. L'Ang II reduisait aussi l'effet de l'ECA2 sur les niveaux de ERK1/2, l'activite proteolytique d'ECA2 et l'expression d'adam17 chez les FCH. De plus, ces reductions provoquees par l'Ang II pouvaient etre attenuees par le valsartan, un antagoniste du AT1R. En conclusion, ces donnees contribuent a clarifier comment l'ECA2 et l'Ang II interagissent pour reguler la MMP-2 et controler le remodelage tissulaire lors de maladies cardiaques. [Traduit par la Redaction] Mots-cles : angiotensine II, enzyme de conversion de l'angiotensine II, metalloprotease de la matrice-2, fibroblastes cardiaques humains., Introduction Angiotensin II (Ang II) is a main regulator of renin-angiotensin system (RAS) and functions to repair and remodel tissues by stimulating inflammation, cell growth, apoptosis, fibrogenesis, and differentiation (Ruiz-Ortega [...]

Prostate cancer has its highest incidence and is becoming a major concern. Many studies have shown that traditional Chinese medicine exhibited antitumor responses. Quercetin, a natural polyphenolic compound, has been shown to induce apoptosis in many human cancer cell lines. Although numerous evidences show multiple possible signaling pathways of quercetin in apoptosis, there is no report to address the role of endoplasmic reticulum (ER) stress in quercetin-induced apoptosis in PC-3 cells. The purpose of this study was to investigate the effects of quercetin on the induction of the apoptotic pathway in human prostate cancer PC-3 cells. Cells were treated with quercetin for 24 and 48 h and at various doses (50-200 μM), and cell morphology and viability decreased significantly in dose-dependent manners. Flow cytometric assay indicated that quercetin at 150 μM caused G0/G1 phase arrest (31.4-49.7%) and sub-G1 phase cells (19.77%) for 36 h treatment and this effect is a time-dependent manner. Western blotting analysis indicated that quercetin induces the G0/G1 phase arrest via decreasing the levels of CDK2, cyclins E, and D proteins. Quercetin also stimulated the protein expression of ATF, GRP78, and GADD153 which is a hall marker of ER stress. Furthermore, PC-3 cells after incubation with quercetin for 48 h showed an apoptotic cell death and DNA damage which are confirmed by DAPI and Comet assays, leading to decrease the antiapoptotic Bcl-2 protein and level of ΔΨm, and increase the proapoptotic Bax protein and the activations of caspase-3, -8, and -9. Moreover, quercetin promoted the trafficking of AIF protein released from mitochondria to nuclei. These data suggest that quercetin may induce apoptosis by direct activation of caspase cascade through mitochondrial pathway and ER stress in PC-3 cells. [ABSTRACT FROM AUTHOR]