Obesity-related disorders are associated with the development of ischemic heart disease. Adiponectin is a circulating adipose-derived cytokine that is downregulated in obese individuals and after myocardial infarction. Here, we examine the role of adiponectin in myocardial remodeling in response to acute injury. Ischemia-reperfusion in adiponectin-deficient (APN-KO) mice resulted in increased myocardial infarct size, myocardial apoptosis and tumor necrosis factor (TNF)-alpha expression compared with wild-type mice. Administration of adiponectin diminished infarct size, apoptosis and TNF-alpha production in both APN-KO and wild-type mice. In cultured cardiac cells, adiponectin inhibited apoptosis and TNF-alpha production. Dominant negative AMP-activated protein kinase (AMPK) reversed the inhibitory effects of adiponectin on apoptosis but had no effect on the suppressive effect of adiponectin on TNF-alpha production. Adiponectin induced cyclooxygenase (COX)-2-dependent synthesis of prostaglandin E(2) in cardiac cells, and COX-2 inhibition reversed the inhibitory effects of adiponectin on TNF-alpha production and infarct size. These data suggest that adiponectin protects the heart from ischemia-reperfusion injury through both AMPK- and COX-2-dependent mechanisms.

Although increased external load initially induces cardiac hypertrophy with preserved contractility, sustained overload eventually leads to heart failure through poorly understood mechanisms. Here we describe a conditional transgenic system in mice characterized by the sequential development of adaptive cardiac hypertrophy with preserved contractility in the acute phase and dilated cardiomyopathy in the chronic phase following the induction of an activated Akt1 gene in the heart. Coronary angiogenesis was enhanced during the acute phase of adaptive cardiac growth but reduced as hearts underwent pathological remodeling. Enhanced angiogenesis in the acute phase was associated with mammalian target of rapamycin-dependent induction of myocardial VEGF and angiopoietin-2 expression. Inhibition of angiogenesis by a decoy VEGF receptor in the acute phase led to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Thus, both heart size and cardiac function are angiogenesis dependent, and disruption of coordinated tissue growth and angiogenesis in the heart contributes to the progression from adaptive cardiac hypertrophy to heart failure.

Patients with diabetes and other obesity-linked conditions have increased susceptibility to cardiovascular disorders. The adipocytokine adiponectin is decreased in patients with obesity-linked diseases. Here, we found that pressure overload in adiponectin-deficient mice resulted in enhanced concentric cardiac hypertrophy and increased mortality that was associated with increased extracellular signal-regulated kinase (ERK) and diminished AMP-activated protein kinase (AMPK) signaling in the myocardium. Adenovirus-mediated supplemention of adiponectin attenuated cardiac hypertrophy in response to pressure overload in adiponectin-deficient, wild-type and diabetic db/db mice. In cultures of cardiac myocytes, adiponectin activated AMPK and inhibited agonist-stimulated hypertrophy and ERK activation. Transduction with a dominant-negative form of AMPK reversed these effects, suggesting that adiponectin inhibits hypertrophic signaling in the myocardium through activation of AMPK signaling. Adiponectin may have utility for the treatment of hypertrophic cardiomyopathy associated with diabetes and other obesity-related diseases.

Adiponectin is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Here, we investigated whether adiponectin regulates angiogenic processes in vitro and in vivo.

Resveratrol may protect against metabolic disease through activating SIRT1 deacetylase. Because we have recently defined AMPK activation as a key mechanism for the beneficial effects of polyphenols on hepatic lipid accumulation, hyperlipidemia, and atherosclerosis in type 1 diabetic mice, we hypothesize that polyphenol-activated SIRT1 acts upstream of AMPK signaling and hepatocellular lipid metabolism. Here we show that polyphenols, including resveratrol and the synthetic polyphenol S17834, increase SIRT1 deacetylase activity, LKB1 phosphorylation at Ser 428 , and AMPK activity. Polyphenols substantially prevent the impairment in phosphorylation of AMPK and its downstream target, ACC (acetyl-CoA carboxylase), elevation in expression of FAS (fatty acid synthase), and lipid accumulation in human HepG2 hepatocytes exposed to high glucose. These effects of polyphenols are largely abolished by pharmacological and genetic inhibition of SIRT1, suggesting that the stimulation of AMPK and lipid-lowering effect of polyphenols depend on SIRT1 activity. Furthermore, adenoviral overexpression of SIRT1 stimulates the basal AMPK signaling in HepG2 cells and in the mouse liver. AMPK activation by SIRT1 also protects against FAS induction and lipid accumulation caused by high glucose. Moreover, LKB1, but not CaMKK␤, is required for activation of AMPK by polyphenols and SIRT1. These findings suggest that SIRT1 functions as a novel upstream regulator for LKB1/AMPK signaling and plays an essential role in the regulation of hepatocyte lipid metabolism. Targeting SIRT1/LKB1/ AMPK signaling by polyphenols may have potential therapeutic implications for dyslipidemia and accelerated atherosclerosis in diabetes and age-related diseases. AMPK (AMP-activated protein kinase)2 serves as a sensor of cellular energy status, being activated by increased AMP/ATP ratio or by the upstream kinases, LKB1 (the tumor suppressor kinase), CaMKK␤ (Ca 2ϩ /calmodulin-dependent protein kinase kinase ␤), and TAK1 (transforming growth factor-␤-activated kinase-1) (1-7). Our previous studies demonstrated that dysfunction of hepatic AMPK induced by hyperglycemia represents a key mechanism for hepatic lipid accumulation and hyperlipidemia associated with diabetes (8, 9). Also, metformin, an antidiabetic drug, lowers systemic and hepatic lipids via activating LKB1/AMPK signaling (2, 8, 10). Our recent studies with human hepatocytes and type 1 diabetic LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice have shown that polyphenols strongly stimulate hepatic AMPK and reduce lipid accumulation, which in turn attenuates hyperlipidemia and atherosclerosis in diabetic mice (9). Therefore, AMPK activation by polyphenols or metformin may be at least partially responsible for their therapeutic benefits on hyperlipidemia in diabetes (2,8,9). Resveratrol also stimulates AMPK in neurons (11). However, rapid activation of AMPK by polyphenols has been shown to be independent of altered adenine nucleotide levels (9, 11). Also, resveratrol activates AMPK in intact cells via an indirect mech...

In contrast to the well-established role of oxidative muscle fibers in regulating whole-body metabolism, little is known about the function of fast/glycolytic muscle fibers in these processes. Here, we generated a skeletal muscle-specific, conditional transgenic mouse expressing a constitutively active form of Akt1. Transgene activation led to muscle hypertrophy due to the growth of type IIb muscle fibers, which was accompanied by an increase in strength. Akt1 transgene induction in diet-induced obese mice led to reductions in body weight and fat mass, resolution of hepatic steatosis, and improved metabolic parameters. Akt1-mediated skeletal muscle growth opposed the effects of a high-fat/high-sucrose diet on transcript expression patterns in the liver and increased hepatic fatty acid oxidation and ketone body production. Our findings indicate that an increase in fast/glycolytic muscle mass can result in the regression of obesity and metabolic improvement through its ability to alter fatty acid oxidation in remote tissues.

Abstract-Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD. Key Words: SR-BI/apolipoprotein E knockout mice Ⅲ atherosclerosis Ⅲ myocardial infarction Ⅲ coronary artery disease Ⅲ lipoprotein metabolism O ne of the best understood risk factors for coronary artery atherosclerosis, a leading cause of myocardial infarction (MI) and death, is hypercholesterolemia. Unfortunately, few hypercholesterolemia and atherosclerosis rodent models spontaneously develop MIs and cardiac dysfunction. Fat-fed LDL receptor (LDLR) knockout (KO) 1 and chow-fed apolipoprotein E (apoE) KO mice, 2-4 standard models for hypercholesterolemia/atherosclerosis, do not usually exhibit MI or reduced lifespans; although 24-to 40-week-old, fat-fed apoE KO mice can develop coronary arterial plaques and, occasionally, small areas of myocardial fibrosis. 4,5 ApoE/LDLR double KO mice fed a high-fat/high-cholesterol diet for 7 months have occlusive coronary arterial atherosclerotic lesions and some associated perivascular myocardial scarring. 6 Severe stress exacerbates the small ECG abnormalities seen in these mice at rest and can induce endothelin-dependent MIs, 6 although such MIs were not reported to be lethal. Dahl salt-sensitive, hypertensive rats expressing high levels of human cholesteryl ester transfer protein 7 and atherosclerosisprone male JCR:LA-corpulent rats, 8 which have hyperlipidemia and atherosclerosis, develop coronary artery lesions and MIs.It would be useful to have additional, genetically manipulable, murine models of...

Although signaling mechanisms inducing cardiac hypertrophy have been extensively studied, little is known about the mechanisms that reverse cardiac hypertrophy. Here, we describe the existence of a similar Akt/forkhead signaling axis in cardiac myocytes in vitro and in vivo, which is regulated by insulin, insulinlike growth factor (IGF), stretch, pressure overload, and angiotensin II stimulation. FOXO3a gene transfer prevented both IGF and stretch-induced hypertrophy in rat neonatal cardiac myocyte cultures in vitro. Transduction with FOXO3a also caused a significant reduction in cardiomyocyte size in mouse hearts in vivo. Akt/FOXO signaling regulated the expression of multiple atrophy-related genes "atrogenes," including the ubiquitin ligase atrogin-1 (MAFbx). In cardiac myocyte cultures, transduction with constitutively active Akt or treatment with IGF suppressed atrogin-1 mRNA expression, whereas transduction with FOXO3a stimulated its expression. FOXO3a transduction activated the atrogin-1 promoter in both cultured myocytes and mouse heart. Thus, in cardiomyocytes, as in skeletal muscle, FOXO3a activates an atrogene transcriptional program, which retards or prevents hypertrophy and is down-regulated by multiple physiological and pathological stimuli of myocyte growth.Cardiac hypertrophy occurs during normal physiological growth of the organism and as an adaptive response to pressure or volume stress, mutations in cardiac proteins, or metabolic perturbations (1). Hypertrophy is characterized by an increase in cell size, enhanced protein synthesis and, in some cases, reorganization of the sarcomere. In pathological hypertrophy, the increase in cardiac myocyte size is thought to be a compensatory mechanism to diminish wall stresses that result from hypertension, valvular heart disease, or myocardial infarction. Ventricular hypertrophy is associated with a significantly increased risk of heart failure and malignant arrhythmias (2).Multiple signaling pathways contribute to the hypertrophic phenotype (3, 4). A number of studies have shown that the serine-threonine kinase Akt (protein kinase B) is an important regulator of myocyte growth (5) and survival (6). Many stimuli activate Akt including the growth factors insulin and IGF 1 (7), angiotensin II (8), and mechanical stress (9). Constitutive overexpression of Akt in transgenic mice can lead to enhanced contractility (10), cytoprotection (11), and pathological cardiac hypertrophy (12, 13). Akt signaling is also an important determinant of physiological heart growth and coordinates heart size with body size as the nutritional status of the organism varies (7). The growth factor/Akt signaling pathway up-regulates protein expression through mechanisms involving the activation of the mammalian target of rapamycin (13), eukaryotic initiation factor 4E-binding proteins (14), p70S6k (7), and the inhibition of GSK3␤ (15).Relatively little is known about the mechanisms that negatively regulate the hypertrophic phenotype. Hearts undergo a reduction in size in response to a...