Therapeutic angiogenesis for patients with no-option critical limb ischemia by adipose-derived regenerative cells: TACT-ADRC multicenter trial.

BACKGROUND: Patients with critical limb ischemia (CLI) still have a high rate of lower limb amputation, which is associated with not only a decrease in quality of life but also poor life prognosis. Implantation of adipose-derived regenerative cells (ADRCs) has an angiogenic potential for patients with limb ischemia. OBJECTIVES: We investigated safety, feasibility, and efficacy of therapeutic angiogenesis by cell transplantation (TACT) of ADRCs for those patients in multicenter clinical trial in Japan. METHODS: The TACT-ADRC multicenter trial is a prospective, interventional, open-labeled study. Patients with CLI (Fontaine class III-IV) who have no other option for standard revascularization therapy were enrolled in this study. Thirty-four target ischemic limbs of 29 patients were received freshly isolated autologous ADRCs implantation. RESULTS: The overall survival rate at a post-operative period and at 6 months follow-up was 100% at any time points. As a primary endpoint for efficacy evaluation, 32 limbs out of 34 (94.1%) were free from major amputation for 6 months. Numerical rating scale (from 6 to 1) as QOL score, ulcer size (from 317 mm2 at to 109 mm2), and 6-min walking distance (from 255 to 369 m) improved in 90.6%, 83.3%, and 72.2% patients, respectively. CONCLUSIONS: Implantation of autologous ADRCs could be safe and effective for the achievement of therapeutic angiogenesis in the multicenter settings, as a result in no major adverse event, optimal survival rate, and limb salvage for patients with no-conventional option against critical limb ischemia. TRN: jRCTb040190118; Date: Nov. 24th, 2015.

Significance of mild thrombocytopenia in maintenance hemodialysis patients; a retrospective cohort study.

Platelet activation in the hemodialysis (HD) circuit often causes thrombocytopenia. However, its clinical and pathophysiological significance has rarely been explored. Herein, we investigated the predictive value of thrombocytopenia for cardiovascular events (CVE) in maintenance HD patients and attempted to explore its mechanistic background considering recent knowledge of platelet dynamics. We conducted a retrospective cohort study on HD patients with the composite primary endpoint of predicting CVE, i.e., myocardial infarction, ischemic stroke, and cardiovascular death. Baseline clinical data were analyzed and explored. Multivariate Cox regression analysis showed that platelet decrease was independently associated with CVE. Thrombocytopenia was correlated with the disuse of antiplatelet therapy (APT) and macrocytosis. These findings are possibly associated with platelet activation and senescent hematopoiesis. The prognostic significance of thrombocytopenia was more prominent in patients undergoing APT, implying the presence of APT-resistant platelets in such patients. To fully explain these results, we hypothesized that HD-activated platelets induce the biological aging of hematopoiesis, which is presumably extramedullary in the lung, where activated platelets could deliver massive amounts of inflammatory cytokines and reactive oxidative species. This results in the production of qualitatively altered and hyper-reactive platelets, a process that could form a vicious cycle that induces CVE-associated thrombocytopenia. Further investigations focusing on the dynamics of the biological aging of platelets in HD patients are warranted.

Brain-derived neurotrophic factor protects against cardiac dysfunction after myocardial infarction via a central nervous system-mediated pathway.

OBJECTIVE: The central nervous system is thought to influence the regulation of the cardiovascular system in response to humoral and neural signals from peripheral tissues, but our understanding of the molecular mechanisms involved is still quite limited. METHODS AND RESULTS: Here, we demonstrate a central nervous system-mediated mechanism by which brain-derived neurotrophic factor (BDNF) has a protective effect against cardiac remodeling after myocardial infarction (MI). We generated conditional BDNF knockout mice, in which expression of BDNF was systemically reduced, by using the inducible Cre-loxP system. Two weeks after MI was induced surgically in these mice, systolic function was significantly impaired and cardiac size was markedly increased in conditional BDNF knockout mice compared with controls. Cardiomyocyte death was increased in these mice, along with decreased expression of survival molecules. Deletion of the BDNF receptor (tropomyosin-related kinase B) from the heart also led to the exacerbation of cardiac dysfunction after MI. The plasma levels of BDNF were markedly increased after MI, and this increase was associated with the upregulation of BDNF expression in the brain, but not in the heart. Ablation of afferent nerves from the heart or genetic disruption of neuronal BDNF expression inhibited the increase of plasma BDNF after MI and led to the exacerbation of cardiac dysfunction. Peripheral administration of BDNF significantly restored the cardiac phenotype of neuronal BDNF-deficient mice. CONCLUSIONS: These results suggest that BDNF expression is upregulated by neural signals from the heart after MI and then protects the myocardium against ischemic injury.

p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload.

Cardiac hypertrophy occurs as an adaptive response to increased workload to maintain cardiac function. However, prolonged cardiac hypertrophy causes heart failure, and its mechanisms are largely unknown. Here we show that cardiac angiogenesis is crucially involved in the adaptive mechanism of cardiac hypertrophy and that p53 accumulation is essential for the transition from cardiac hypertrophy to heart failure. Pressure overload initially promoted vascular growth in the heart by hypoxia-inducible factor-1 (Hif-1)-dependent induction of angiogenic factors, and inhibition of angiogenesis prevented the development of cardiac hypertrophy and induced systolic dysfunction. Sustained pressure overload induced an accumulation of p53 that inhibited Hif-1 activity and thereby impaired cardiac angiogenesis and systolic function. Conversely, promoting cardiac angiogenesis by introducing angiogenic factors or by inhibiting p53 accumulation developed hypertrophy further and restored cardiac dysfunction under chronic pressure overload. These results indicate that the anti-angiogenic property of p53 may have a crucial function in the transition from cardiac hypertrophy to heart failure.

Inhibition of semaphorin as a novel strategy for therapeutic angiogenesis.

RATIONALE: The axon-guiding molecules known as semaphorins and their receptors (plexins) regulate the vascular pattern and play an important role in the development of vascular network during embryogenesis. Semaphorin (Sema)3E is one of the class 3 semaphorins, and plexinD1 is known to be its receptor. Although these molecules have a role in embryonic vascular development, it remains unclear whether the Sema3E/plexinD1 axis is involved in postnatal angiogenesis. OBJECTIVE: The objective of this study was to elucidate the role of Sema3E/plexinD1 in postnatal angiogenesis. METHODS AND RESULTS: Sema3E inhibited cell growth and tube formation by suppressing the vascular endothelial growth factor (VEGF) signaling pathway. Expression of Sema3E and plexinD1 was markedly upregulated in ischemic limbs of mice (2.5- and 4.5-fold increase for Sema3E and plexinD1, respectively), and inhibition of this pathway by introduction of the plexinD1-Fc gene or disruption of Sema3E led to a significant increase of blood flow recovery (1.6- and 1.5-fold increase for the plexinD1-Fc gene treatment and Sema3E disruption, respectively). Hypoxia activated the tumor suppressor protein p53, thereby upregulating Sema3E expression. Expression of p53 and Sema3E was enhanced in diabetic mice compared with normal mice (2- and 1.3-fold increase for p53 and Sema3E, respectively). Consequently, neovascularization after VEGF treatment was poor in the ischemic tissues of diabetic mice, whereas treatment with VEGF plus plexinD1-Fc markedly improved neovascularization. CONCLUSIONS: These results indicate that inhibition of Sema3E may be a novel strategy for therapeutic angiogenesis, especially when VEGF is ineffective.

Role of Jagged1 in arterial lesions after vascular injury.

OBJECTIVE: Impaired regeneration of endothelial cells (EC) and overactivity of vascular smooth muscle cells (VSMC) are hallmarks of the arterial lesions associated with aging. The occurrence of 2 opposing cellular processes in the same arterial milieu makes pharmaceutical treatment difficult to develop. We previously reported that endothelial expression of a Notch ligand (Jagged1) was reduced in aged animals and that growth of the neointima was enhanced in these animals. METHODS AND RESULTS: Similar to aged animals, Tie2-cre(+) Jagged1(lox/+) mice (with heterologous knockout of Jagged1 in EC) showed exaggerated intimal and medial thickening after carotid artery ligation. Unexpectedly, these mice showed little increase of Jagged1 expression not only in EC but also in VSMC, in contrast to a significant upregulation of Jagged1 in wild-type arteries after ligation. Coculture of VSMC with Jagged1-null EC resulted in the transition of VSMC from the contractile to the synthetic phenotype, along with decreased Jagged1 expression by VSMC. Conversely, overexpression of Jagged1 by EC or VSMC was shown to prevent the unfavorable phenotypic transition of VSMC, under both monoculture and coculture conditions. CONCLUSIONS: These findings suggest a unidirectional effect of Jagged1 on both EC and VSMC that contributes to inhibition of arterial lesions after vascular injury. Our data also indicate that Jagged1 may be a novel therapeutic target for aging-related vascular diseases.

Reduced nitric oxide causes age-associated impairment of circadian rhythmicity.

Impairment of circadian rhythmicity in the elderly has been suggested to cause age-associated diseases such as atherosclerosis and hypertension. Endothelium-derived nitric oxide (NO) is a critical regulator of cardiovascular homeostasis, but its production declines with aging, thereby inducing vascular dysfunction. We show here that impaired circadian rhythmicity is related to a decrease of NO production with aging. Treatment with an NO donor significantly upregulated the promoter activity of the clock gene Period via the cAMP response element-dependent and the E-box enhancer element-dependent pathways. Both phosphorylation and S-nitrosylation by NO are involved in this upregulation. In aged animals, endothelial NO synthase activity was markedly decreased during the daytime, along with impairment of clock gene expression and the circadian variation in blood pressure. Treatment of aged animals with an NO donor significantly improved the impairments. Inhibition of NO synthase activity also led to impairment of clock gene expression and blood pressure rhythm. These results suggest that NO is a key regulator of the circadian clock in the cardiovascular system and may be a novel target for the treatment of age-associated alteration of circadian rhythms.

Vascular endothelial growth factor receptor-1 regulates postnatal angiogenesis through inhibition of the excessive activation of Akt.

Vascular endothelial growth factor (VEGF) binds both VEGF receptor-1 (VEGFR-1) and VEGF receptor-2 (VEGFR-2). Activation of VEGFR-2 is thought to play a major role in the regulation of endothelial function by VEGF. Recently, specific ligands for VEGFR-1 have been reported to have beneficial effects when used to treat ischemic diseases. However, the role of VEGFR-1 in angiogenesis is not fully understood. In this study, we showed that VEGFR-1 performs "fine tuning" of VEGF signaling to induce neovascularization. We examined the effects of retroviral vectors expressing a small interference RNA that targeted either the VEGFR-1 gene or the VEGFR-2 gene. Deletion of either VEGFR-1 or VEGFR-2 reduced the ability of endothelial cells to form capillaries. Deletion of VEGFR-1 markedly reduced endothelial cell proliferation and induced premature senescence of endothelial cells. In contrast, deletion of VEGFR-2 significantly impaired endothelial cell survival. When VEGFR-1 expression was blocked, VEGF constitutively activated Akt signals and thus induced endothelial cell senescence via a p53-dependent pathway. VEGFR-1(+/-) mice exhibited an increase of endothelial Akt activity and showed an impaired neovascularization in response to ischemia, and this impairment was ameliorated in VEGFR-1(+/-) Akt1(+/-) mice. These results suggest that VEGFR-1 plays a critical role in the maintenance of endothelial integrity by modulating the VEGF/Akt signaling pathway.

Protective role of SIRT1 in diabetic vascular dysfunction.

OBJECTIVE: Calorie restriction (CR) prolongs the lifespan of various species, ranging from yeasts to mice. In yeast, CR extends the lifespan by increasing the activity of silencing information regulator 2 (Sir2), an NAD(+)-dependent deacetylase. SIRT1, a mammalian homolog of Sir2, has been reported to downregulate p53 activity and thereby prolong the lifespan of cells. Although recent evidence suggests a link between SIRT1 activity and metabolic homeostasis during CR, its pathological role in human disease is not yet fully understood. METHODS AND RESULTS: Treatment of human endothelial cells with high glucose decreases SIRT1 expression and thus activates p53 by increasing its acetylation. This in turn accelerates endothelial senescence and induces functional abnormalities. Introduction of SIRT1 or disruption of p53 inhibits high glucose-induced endothelial senescence and dysfunction. Likewise, activation of Sirt1 prevents the hyperglycemia-induced vascular cell senescence and thereby protects against vascular dysfunction in mice with diabetes. CONCLUSIONS: These findings represent a novel mechanism of vascular cell senescence induced by hyperglycemia and suggest a protective role of SIRT1 in the pathogenesis of diabetic vasculopathy.

Cellular senescence impairs circadian expression of clock genes in vitro and in vivo.

Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent cells. When young cells were implanted into young mice or old mice, the implanted cells were effectively entrained by the circadian rhythm of the recipients. In contrast, the entrainment of implanted senescent cells was markedly impaired. These results suggest that senescence decreases the ability of cells to transmit circadian signals to their clocks and that regulation of clock gene expression may be a novel strategy for the treatment of age-associated impairment of circadian rhythmicity.

Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization.

The discovery of bone marrow-derived endothelial progenitors in the peripheral blood has promoted intensive studies on the potential of cell therapy for various human diseases. Accumulating evidence has suggested that implantation of bone marrow mononuclear cells effectively promotes neovascularization in ischemic tissues. It has also been reported that the implanted cells are incorporated not only into the newly formed vessels but also secrete angiogenic factors. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. We enrolled 29 "no-option" patients with critical limb ischemia and treated ischemic limbs by implantation of peripheral mononuclear cells. Cell therapy using peripheral mononuclear cells was very effective for the treatment of limb ischemia, and its efficacy was associated with increases in the plasma levels of angiogenic factors, in particular interleukin-1beta (IL-1beta). We then examined an experimental model of limb ischemia using IL-1beta-deficient mice. Implantation of IL-1beta-deficient mononuclear cells improved tissue ischemia as efficiently as that of wild-type cells. Both wild-type and IL-1beta-deficient mononuclear cells increased expression of IL-1beta and thus induced angiogenic factors in muscle cells of ischemic limbs to a similar extent. In contrast, inability of muscle cells to secrete IL-1beta markedly reduces induction of angiogenic factors and impairs neovascularization by cell implantation. Implanted cells do not secret angiogenic factors sufficient for neovascularization but, instead, stimulate muscle cells to produce angiogenic factors, thereby promoting neovascularization in ischemic tissues. Further studies will allow us to develop more effective treatments for ischemic vascular disease.

Angiotensin II induces premature senescence of vascular smooth muscle cells and accelerates the development of atherosclerosis via a p21-dependent pathway.

BACKGROUND: Angiotensin II (Ang II) has been reported to contribute to the pathogenesis of various human diseases including atherosclerosis, and inhibition of Ang II activity has been shown to reduce the morbidity and mortality of cardiovascular diseases. We have previously demonstrated that vascular cell senescence contributes to the pathogenesis of atherosclerosis; however, the effects of Ang II on vascular cell senescence have not been examined. METHODS AND RESULTS: Ang II significantly induced premature senescence of human vascular smooth muscle cells (VSMCs) via the p53/p21-dependent pathway in vitro. Inhibition of this pathway effectively suppressed induction of proinflammatory cytokines and premature senescence of VSMCs by Ang II. Ang II also significantly increased the number of senescent VSMCs and induced the expression of proinflammatory molecules and of p21 in a mouse model of atherosclerosis. Loss of p21 markedly ameliorated the induction of proinflammatory molecules by Ang II, thereby preventing the development of atherosclerosis. Replacement of p21-deficient bone marrow cells with wild-type cells had little influence on the protective effect of p21 deficiency against the progression of atherogenesis induced by Ang II. CONCLUSIONS: We demonstrated that Ang II promotes vascular inflammation by inducing premature senescence of VSMCs both in vitro and in vivo. Our results suggest a critical role of p21-dependent premature senescence of VSMCs in the pathogenesis of atherosclerosis.

Successful intermuscular implantation of subcutaneous implantable cardioverter defibrillator in a Japanese patient with pectus excavatum.

The entirely subcutaneous implantable cardioverter-defibrillator (ICD) system was developed to provide a life-saving defibrillation therapy that does not affect the heart and vasculature. The subcutaneous ICD is preferred over the transvenous ICD for patients with a history of recurrent infection presenting major life-threatening rhythms. In this case report, we describe the first successful intermuscular implantation of a completely subcutaneous ICD in a Japanese patient with pectus excavatum. There were no associated complications with the device implantation or lead positioning. Further, the defibrillation threshold testing did not pose any problem with the abnormal anatomy of the patient.

Application of hematopoietic cells to therapeutic angiogenesis.

Despite considerable progress in the field of cardiovascular medicine and surgery, ischemic heart disease is still the leading cause of death in advanced countries. In this context, it is no wonder why therapeutic angiogenesis, a way to ameliorate ischemic tissue from suffering dysfunction by increasing new blood vessels, gains so much attention from both clinicians and patients. In this review, we will briefly go through a decade of history in therapeutic angiogenesis including unraveling of its mechanisms, results obtained from clinical trials, and lessons learned from earlier investigations. We will then focus on an emerging, yet rapidly evolving field of hematopoietic cell therapy. Recent excellent studies seem to have brought us to the place where we might save so many patients from burden of ischemia, we should be aware that there are some controversies, and sometimes misunderstandings, regarding how or why this treatment does actually work, and what better way should we explore in order to get the best of its efficacy. With these caveats in mind, we will investigate the works elucidating the mechanisms and clinical efficacies of hematopoietic cell therapy.

Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis.

BACKGROUND: Vascular cells have a finite cell lifespan and eventually enter an irreversible growth arrest, cellular senescence. The functional changes associated with cellular senescence are thought to contribute to human aging and age-related vascular disorders. Ras, an important signaling molecule involved in atherogenic stimuli, is known to promote aging in yeast and cellular senescence in primary human fibroblasts. The aim of this study was to investigate the role of Ras-induced vascular smooth muscle cell (VSMC) senescence in atherogenesis. METHODS AND RESULTS: We introduced an activated ras allele (H-rasV12) into human VSMCs using retroviral infection. Introduction of H-rasV12 induced a growth arrest with phenotypic characteristics of cellular senescence, such as enlarged cell shapes and increases in expression of cyclin-dependent kinase inhibitors and senescence-associated beta-galactosidase (SA-beta-gal) activity. Activation of Ras drastically increased expression of proinflammatory cytokines, in part through extracellular signal-regulated kinase activation. To determine whether Ras activation induces cellular senescence in vivo, we transduced the adenoviral vector encoding H-rasV12 into rat carotid arteries injured by a balloon catheter. Introduction of Ras into the arteries enhanced vascular inflammation and senescence compared with mock-infected injured arteries. Moreover, SA-beta-gal-positive VSMCs were detected in the intima of advanced human atherosclerotic lesions and exhibited increased levels of extracellular signal-regulated kinase activity and proinflammatory cytokine expression. CONCLUSIONS: Our results suggest that atherogenic stimuli mediated by Ras induce VSMC senescence and vascular inflammation, thereby contributing to atherogenesis. This novel mechanism of atherogenesis may provide insights into a new antisenescence treatment for atherosclerosis.

Akt-induced cellular senescence: implication for human disease.

Reduction-of-function mutations in components of the insulin/insulin-like growth factor-1/Akt pathway have been shown to extend the lifespan in organisms ranging from yeast to mice. It has also been reported that activation of Akt induces proliferation and survival of mammalian cells, thereby promoting tumorigenesis. We have recently shown that Akt activity increases with cellular senescence and that inhibition of Akt extends the lifespan of primary cultured human endothelial cells. Constitutive activation of Akt promotes senescence-like arrest of cell growth via a p53/p21-dependent pathway, leading to endothelial dysfunction. This novel role of Akt in regulating the cellular lifespan may contribute to various human diseases including atherosclerosis and diabetes mellitus.

The role of vascular cell senescence in atherosclerosis: antisenescence as a novel therapeutic strategy for vascular aging.

Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence." It has been reported that many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. Recently, senescent vascular cells have been demonstrated in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of proinflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Introduction of telomere malfunction has been shown to lead to vascular dysfunction that promotes atherogenesis, whereas telomere lengthening extends cell lifespan and protects against vascular dysfunction associated with senescence. Indeed, recent studies have demonstrated that telomere attrition occurs in the blood vessels and is associated with human atherosclerosis. More recent evidence suggests that telomere-independent mechanisms are implicated in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby, promotes vascular inflammation in vitro and in vivo. Although a causal link between vascular aging and vascular cell senescence remains elusive, a large body of data is consistent with cellular senescence contributing to age-associated vascular disorders. This review considers the clinical relevance of vascular cell senescence in vivo and discusses the potential of antisenescence therapy for human atherosclerosis.

Notch signaling regulates the lifespan of vascular endothelial cells via a p16-dependent pathway.

Evolutionarily conserved Notch signaling controls cell fate determination and differentiation during development, and is also essential for neovascularization in adults. Although recent studies suggest that the Notch pathway is associated with age-related conditions, it remains unclear whether Notch signaling is involved in vascular aging. Here we show that Notch signaling has a crucial role in endothelial cell senescence. Inhibition of Notch signaling in human endothelial cells induced premature senescence via a p16-dependent pathway. Conversely, over-expression of Notch1 or Jagged1 prolonged the replicative lifespan of endothelial cells. Notch1 positively regulated the expression of inhibitor of DNA binding 1 (Id1) and MAP kinase phosphatase 1 (MKP1), while MKP1 further up-regulated Id1 expression by inhibiting p38MAPK-induced protein degradation. Over-expression of Id1 down-regulated p16 expression, thereby inhibiting premature senescence of Notch1-deleted endothelial cells. These findings indicate that Notch1 signaling has a role in the regulation of endothelial cell senescence via a p16-dependent pathway and suggest that activation of Notch1 could be a new therapeutic target for treating age-associated vascular diseases.

Notch activation mediates angiotensin II-induced vascular remodeling by promoting the proliferation and migration of vascular smooth muscle cells.

Notch signaling is involved in an intercellular communication mechanism that is essential for coordinated cell fate determination and tissue morphogenesis. The biological effects of Notch signaling are context-dependent. We investigated the functional and hierarchical relationship between angiotensin (Ang) II receptor signaling and Notch signaling in vascular smooth muscle cells (VSMCs). A fluorogenic substrate assay revealed directly that the enzymatic activity of γ-secretase was enhanced after 10 min of Ang II stimulation in HEK293 cells expressing Ang II type 1 receptor. Notch cleavage by γ-secretase was consistently induced and peaked at 10 min after Ang II stimulation, and the Ang II-stimulated increase in Notch intracellular domain production was significantly suppressed by treatment with the γ-secretase inhibitor DAPT. Treatment with DAPT also significantly reduced the Ang II-stimulated proliferation and migration of human aortic VSMCs, as revealed by BrdU incorporation and the Boyden chamber assay, respectively. Systemic administration of the γ-secretase inhibitor dibenzazepine reduced Ang II-induced medial thickening and perivascular fibrosis in the aortas of wild-type mice. These findings suggest that the hierarchical Ang II receptor-Notch signaling pathway promotes the proliferation and migration of VSMCs, and thereby contributes to the progression of vascular remodeling.

p53-induced adipose tissue inflammation is critically involved in the development of insulin resistance in heart failure.

Several clinical studies have shown that insulin resistance is prevalent among patients with heart failure, but the underlying mechanisms have not been fully elucidated. Here, we report a mechanism of insulin resistance associated with heart failure that involves upregulation of p53 in adipose tissue. We found that pressure overload markedly upregulated p53 expression in adipose tissue along with an increase of adipose tissue inflammation. Chronic pressure overload accelerated lipolysis in adipose tissue. In the presence of pressure overload, inhibition of lipolysis by sympathetic denervation significantly downregulated adipose p53 expression and inflammation, thereby improving insulin resistance. Likewise, disruption of p53 activation in adipose tissue attenuated inflammation and improved insulin resistance but also ameliorated cardiac dysfunction induced by chronic pressure overload. These results indicate that chronic pressure overload upregulates adipose tissue p53 by promoting lipolysis via the sympathetic nervous system, leading to an inflammatory response of adipose tissue and insulin resistance.