Resveratrol induces mitochondrial biogenesis and ameliorates Ang II-induced cardiac remodeling in transgenic rats harboring human renin and angiotensinogen genes.
ABSTRACT There is compelling evidence to indicate an important role for increased local renin-angiotensin system activity in the pathogenesis of cardiac hypertrophy and heart failure. Resveratrol is a natural polyphenol that activates SIRT1, a novel cardioprotective and longevity factor having NAD(+)-dependent histone deacetylase activity. We tested the hypothesis whether resveratrol could prevent from angiotensin II (Ang II)-induced cardiovascular damage. Four-week-old double transgenic rats harboring human renin and human angiotensinogen genes (dTGR) were treated for 4 weeks either with SIRT1 activator resveratrol or SIRT1 inhibitor nicotinamide. Untreated dTGR and their normotensive Sprague-Dawley control rats (SD) received vehicle. Untreated dTGR developed severe hypertension as well as cardiac hypertrophy, and showed pronounced cardiovascular mortality compared with normotensive SD rats. Resveratrol slightly but significantly decreased blood pressure, ameliorated cardiac hypertrophy and prevented completely Ang II-induced mortality, whereas nicotinamide increased blood pressure without significantly influencing cardiac hypertrophy or survival. Resveratrol decreased cardiac ANP mRNA expression and induced cardiac mRNA expressions of mitochondrial biogenesis markers peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), mitochondrial transcription factor (Tfam), nuclear respiratory factor 1 (NRF-1) and cytochrome c oxidase subunit 4 (cox4). Resveratrol dose-dependently increased SIRT1 activity in vitro. Our findings suggest that the beneficial effects of SIRT1 activator resveratrol on Ang II-induced cardiac remodeling are mediated by blood pressure-dependent pathways and are linked to increased mitochondrial biogenesis.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: Altered cell metabolism is inherently connected with pathological conditions including cancer and viral infections. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma (KS). KS tumour cells display features of lymphatic endothelial differentiation and in their vast majority are latently infected with KSHV, while a small number are lytically infected, producing virions. Latently infected cells express only a subset of viral genes, mainly located within the latency-associated region, among them 12 microRNAs. Notably, the metabolic properties of KSHV-infected cells closely resemble the metabolic hallmarks of cancer cells. However, how and why KSHV alters host cell metabolism remains poorly understood. Here, we investigated the effect of KSHV infection on the metabolic profile of primary dermal microvascular lymphatic endothelial cells (LEC) and the functional relevance of this effect. We found that the KSHV microRNAs within the oncogenic cluster collaborate to decrease mitochondria biogenesis and to induce aerobic glycolysis in infected cells. KSHV microRNAs expression decreases oxygen consumption, increase lactate secretion and glucose uptake, stabilize HIF1α and decreases mitochondria copy number. Importantly this metabolic shift is important for latency maintenance and provides a growth advantage. Mechanistically we show that KSHV alters host cell energy metabolism through microRNA-mediated down regulation of EGLN2 and HSPA9. Our data suggest that the KSHV microRNAs induce a metabolic transformation by concurrent regulation of two independent pathways; transcriptional reprograming via HIF1 activation and reduction of mitochondria biogenesis through down regulation of the mitochondrial import machinery. These findings implicate viral microRNAs in the regulation of the cellular metabolism and highlight new potential avenues to inhibit viral latency.PLoS Pathogens 09/2014; 10(9):e1004400. · 8.14 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural polyphenolic compound that exists in Polygonum cuspidatum, grapes, peanuts and berries, as well as their manufactured products, especially red wine. Resveratrol is a pharmacologically active compound that interacts with multiple targets in a variety of cardiovascular disease models to exert protective effects or induce a reduction in cardiovascular risks parameters. This review attempts to primarily serve to summarize the current research findings regarding the putative cardioprotective effects of resveratrol and the molecular pathways underlying these effects. One intent is to hopefully provide a relatively comprehensive resource for clues that may prompt ideas for additional mechanistic studies which might further elucidate and strengthen the role of the stilbene family of compounds in cardiovascular disease and cardioprotection. Models systems that incorporate a significant functional association with tissues outside of the cardiovascular system proper, such as adipose (cell culture, obesity models) and pancreatic (diabetes) tissues, were reviewed, and the molecular pathways and/or targets related to these models and influenced by resveratrol are discussed. Because the body of work encompassing the stilbenes and other phytochemicals in the context of longevity and the ability to presumably mitigate a plethora of afflictions is replete with conflicting information and controversy, especially so with respect to the human response, we tried to remain as neutral as possible in compiling and presenting the more current data with minimal commentary, permitting the reader free reign to extract the knowledge most helpful to their own investigations.Pharmacological Research 08/2014; · 3.98 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Polyphenols, ubiquitously present in fruits and vegetables, have been traditionally viewed as antioxidant molecules. Such contention emerged, mainly from their well established in vitro ability to scavenge free radicals and other reactive oxygen species (ROS). During the last decade, however, increasing evidence has emerged supporting the ability of certain polyphenols to also exert numerous ROS-scavenging independent actions. Although the latter can comprise the whole cell, particular attention has been placed on the ability of polyphenols to act, whether favorably or not, on a myriad of mitochondrial processes. Thus, some particular polyphenols are now recognized as molecules capable of modulating pathways that define mitochondrial biogenesis (i.e., inducing sirtuins), mitochondrial membrane potential (i.e., mitochondrial permeability transition pore opening and uncoupling effects), mitochondrial electron transport chain and ATP synthesis (i.e., modulating complexes I to V activity), intra-mitochondrial oxidative status (i.e., inhibiting/inducing ROS formation/removal enzymes), and ultimately mitochondrially-triggered cell death (i.e., modulating intrinsic-apoptosis). The present review describes recent evidence on the ability of some polyphenols to modulate each of the formerly mentioned pathways, and discusses on how, by acting on such mitochondrial processes, polyphenols may afford protection against those mitochondrial damaging events that appear to be key in the cellular toxicity induced by various xenobiotics as well as that seen during the development of several ROS-related diseases.Archives of Biochemistry and Biophysics 05/2014; · 3.04 Impact Factor