stilbenes and Atrial-Remodeling

Chronic increases in blood flow in resistance arteries induce outward remodeling associated with increased wall thickness and endothelium-mediated dilatation. This remodeling is essential for collateral arteries growth following occlusion of a large artery. As estrogens have a major role in this remodeling, we hypothesized that resveratrol, described as possessing phytoestrogen properties, could improve remodeling in ovariectomized rats.. Blood flow was increased in vivo in mesenteric arteries after ligation of adjacent arteries in 3-month old ovariectomized rats treated with resveratrol (5 or 37.5 mg/kg per day: RESV5 or RESV37.5) or vehicle. After 2 weeks arterial structure and function were measured in vitro in high flow (HF) and normal flow (NF) arteries isolated from each rat.. Arterial diameter was greater in HF than in NF arteries in ovariectomized rats treated with RESV5 or RESV37.5, not in vehicle-treated rats. In mice lacking estrogen receptor alpha diameter was equivalent in HF and NF arteries whereas in mice treated with RESV5 diameter was greater in HF than in NF vessels. A compensatory increase in wall thickness and a greater phenylephrine-mediated contraction were observed in HF arteries. This was more pronounced in HF arteries from RESV37.5-treated rats. ERK1/2 phosphorylation, involved in hypertrophy and contraction, were higher in RESV37.5-treated rats than in RESV5- and vehicle-treated rats. Endothelium-dependent relaxation was greater in HF than in NF arteries in RESV5-treated rats only. In HF arteries from RESV37.5-treated rats relaxation was increased by superoxide reduction and markers of oxidative stress (p67phox, GP91phox) were higher than in the 2 other groups.. Resveratrol improved flow-mediated outward remodeling in ovariectomized rats thus providing a potential therapeutic tool in menopause-associated ischemic disorders. This effect seems independent of the estrogen receptor alpha. Nevertheless, caution should be taken with high doses inducing excessive contractility and hypertrophy in association with oxidative stress in HF arteries.

Topics: Animals; Atrial Remodeling; Endothelium, Vascular; Female; Membrane Glycoproteins; Mesenteric Arteries; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle Contraction; NADH, NADPH Oxidoreductases; NADPH Oxidase 2; NADPH Oxidases; Nitric Oxide Synthase Type III; Ovariectomy; Oxidative Stress; Phenylephrine; Phosphorylation; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxides; Vasodilator Agents

Cardiac aging is associated with compromised myocardial function and morphology although the underlying mechanism remains elusive. Aldehyde dehydrogenase 2 (ALDH2), an essential mitochondrial enzyme governing cardiac function, displays polymorphism in humans. This study was designed to examine the role of ALDH2 in aging-induced myocardial anomalies. Myocardial mechanical and intracellular Ca(2+) properties were examined in young (4-5 months) and old (26-28 months) wild-type and ALDH2 transgenic mice. Cardiac histology, mitochondrial integrity, O2(-) generation, apoptosis, and signaling cascades, including AMPK activation and Sirt1 level were evaluated. Myocardial function and intracellular Ca(2+) handling were compromised with advanced aging; the effects were accentuated by ALDH2. Hematoxylin and eosin and Masson trichrome staining revealed cardiac hypertrophy and interstitial fibrosis associated with greater left-ventricular mass and wall thickness in aged mice. ALDH2 accentuated aging-induced cardiac hypertrophy but not fibrosis. Aging promoted O2(-) release, apoptosis, and mitochondrial injury (mitochondrial membrane potential, levels of UCP-2 and PGC-1α), and the effects were also exacerbated by ALDH2. Aging dampened AMPK phosphorylation and Sirt1, the effects of which were exaggerated by ALDH2. Treatment with the ALDH2 activator Alda-1 accentuated aging-induced O2(-) generation and mechanical dysfunction in cardiomyocytes, the effects of which were mitigated by cotreatment with activators of AMPK and Sirt1, AICAR, resveratrol, and SRT1720. Examination of human longevity revealed a positive correlation between life span and ALDH2 gene mutation. Taken together, our data revealed that ALDH2 enzyme may accentuate myocardial remodeling and contractile dysfunction in aging, possibly through AMPK/Sirt1-mediated mitochondrial injury.

Topics: Aging; Aldehyde Dehydrogenase; Aldehyde Dehydrogenase, Mitochondrial; AMP-Activated Protein Kinases; Animals; Apoptosis; Atrial Remodeling; Benzamides; Benzodioxoles; Calcium; Cardiomegaly; Fibrosis; Gene Expression Regulation; Heterocyclic Compounds, 4 or More Rings; Ion Channels; Mice; Mice, Transgenic; Mitochondria, Heart; Mitochondrial Proteins; Myocardial Contraction; Myocardium; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Superoxides; Transcription Factors; Uncoupling Protein 2