Publications by authors named "Jose J Fuster"

38 Publications

Emerging Role of Acquired Mutations and Clonal Hematopoiesis in Atherosclerosis - Beyond Conventional Cardiovascular Risk Factors.

Circ J 2021 Aug 25. Epub 2021 Aug 25.

Centro Nacional de Investigaciones Cardiovasculares [CNIC].

Accumulating evidence suggests that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, as a substantial risk remains even when these factors are apparently managed well. In this context, clonal hematopoiesis has emerged as a new and potent risk factor for atherosclerotic cardiovascular disease and other cardiometabolic conditions. Clonal hematopoiesis typically arises from somatic mutations that confer a competitive advantage to a mutant hematopoietic stem cell, leading to its clonal expansion in the stem cell population and its progeny of blood leukocytes. Human sequencing studies and experiments in mice suggest that clonal hematopoiesis, at least when driven by certain mutations, contributes to accelerated atherosclerosis development. However, the epidemiology, biology and clinical implications of this phenomenon remain incompletely understood. Here, we review the current understanding of the connection between clonal hematopoiesis and atherosclerosis, and highlight knowledge gaps in this area of research.
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http://dx.doi.org/10.1253/circj.CJ-21-0505DOI Listing
August 2021

Clonal Hematopoiesis and Incident Heart Failure Risk: The Clone Wars Reach the Myocardium.

Authors:
José J Fuster

J Am Coll Cardiol 2021 07;78(1):53-55

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2021.04.084DOI Listing
July 2021

Clonal haematopoiesis and atherosclerosis: a chicken or egg question?

Nat Rev Cardiol 2021 Jul;18(7):463-464

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

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http://dx.doi.org/10.1038/s41569-021-00554-zDOI Listing
July 2021

Clonal Hematopoiesis and Risk of Progression of Heart Failure With Reduced Left Ventricular Ejection Fraction.

J Am Coll Cardiol 2021 04;77(14):1747-1759

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

Background: Clonal hematopoiesis driven by somatic mutations in hematopoietic cells, frequently called clonal hematopoiesis of indeterminate potential (CHIP), has been associated with adverse cardiovascular outcomes in population-based studies and in patients with ischemic heart failure (HF) and reduced left ventricular ejection fraction (LVEF). Yet, the impact of CHIP on HF progression, including nonischemic etiology, is unknown.

Objectives: The purpose of this study was to assess the clinical impact of clonal hematopoiesis on HF progression irrespective of its etiology.

Methods: The study cohort comprised 62 patients with HF and LVEF <45% (age 74 ± 7 years, 74% men, 52% nonischemic, and LVEF 30 ± 8%). Deep sequencing was used to detect CHIP mutations with a variant allelic fraction >2% in 54 genes. Patients were followed for at least 3.5 years for various adverse events including death, HF-related death, and HF hospitalization.

Results: CHIP mutations were detected in 24 (38.7%) patients, without significant differences in all-cause mortality (p = 0.151). After adjusting for risk factors, patients with mutations in either DNA methyltransferase 3 alpha (DNMT3A) or Tet methylcytosine dioxygenase 2 (TET2) exhibited accelerated HF progression in terms of death (hazard ratio [HR]: 2.79; 95% confidence interval [CI]: 1.31 to 5.92; p = 0.008), death or HF hospitalization (HR: 3.84; 95% CI: 1.84 to 8.04; p < 0.001) and HF-related death or HF hospitalization (HR: 4.41; 95% CI: 2.15 to 9.03; p < 0.001). In single gene-specific analyses, somatic mutations in DNMT3A or TET2 retained prognostic significance with regard to HF-related death or HF hospitalization (HR: 4.50; 95% CI: 2.07 to 9.74; p < 0.001, for DNMT3A mutations; HR: 3.18; 95% CI: 1.52 to 6.66; p = 0.002, for TET2 mutations). This association remained significant irrespective of ischemic/nonischemic etiology.

Conclusions: Somatic mutations that drive clonal hematopoiesis are common among HF patients with reduced LVEF and are associated with accelerated HF progression regardless of etiology.
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http://dx.doi.org/10.1016/j.jacc.2021.02.028DOI Listing
April 2021

TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.

Cell Rep 2020 10;33(4):108326

Boston University School of Medicine, Boston, MA, USA; Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, VA, USA. Electronic address:

Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of NLRP3 inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.
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http://dx.doi.org/10.1016/j.celrep.2020.108326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856871PMC
October 2020

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.

JCI Insight 2020 03 26;5(6). Epub 2020 Mar 26.

Hematovascular Biology Center, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR2+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.
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http://dx.doi.org/10.1172/jci.insight.135204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213793PMC
March 2020

Clonal hematopoiesis driven by somatic mutations: A new player in atherosclerotic cardiovascular disease.

Atherosclerosis 2020 03 15;297:120-126. Epub 2020 Feb 15.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

The accumulation of acquired mutations is an inevitable consequence of the aging process, but its pathophysiological relevance has remained largely unexplored beyond cancer. Most of these mutations have little or no functional consequences, but in a few rare instances, a mutation may arise that confers a competitive advantage to a stem cell, leading to its clonal expansion. When such a mutation occurs in hematopoietic stem cells, it leads to a situation of clonal hematopoiesis, which has the potential to affect multiple tissues beyond the bone marrow, as the clonal expansion of the mutant stem cell is extended to circulating blood cells and tissue-infiltrating immune cells. Recent genomics and experimental studies have provided support to the notion that this somatic mutation-driven clonal hematopoiesis contributes to vascular inflammation and the development of atherosclerosis and related cardiovascular and cerebrovascular ischemic events. Here, we review our current understanding of this emerging cardiovascular risk modifier and the mechanisms underlying its connection to atherosclerosis development.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.02.008DOI Listing
March 2020

Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD: JACC Review Topic of the Week.

J Am Coll Cardiol 2019 07;74(4):578-586

Cardiovascular Research Center and Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts; Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts; Department of Medicine, Harvard Medical School, Boston, Massachusetts. Electronic address:

The incidence of cardiovascular diseases increases with age and is also correlated with increased inflammatory burden. Recently, human genetics provided a new paradigm linking aging, inflammation, and atherosclerotic cardiovascular disease (ASCVD). Next-generation genetic sequencing of whole blood-derived DNA in humans showed that clonal expansion of hematopoietic cells with somatic mutations in leukemogenic genes was associated with age and correlated with increased mortality. This phenomenon, termed clonal hematopoiesis of indeterminate potential (CHIP), was associated with hematologic malignancy as well as ASCVD independently of age and other traditional risk factors. Because the implication of CHIP with ASCVD, genetic loss-of-function studies of Tet2 and Dnmt3a in murine models have supported a mechanistic role for CHIP in promoting vascular disease. Despite the potential contribution of CHIP to myriad cardiovascular and aging-related diseases, the epidemiology and biology surrounding this phenomenon remains incompletely appreciated and understood, especially as applied to clinical practice and prognostication. Here, the authors review this emerging key risk factor, defining its discovery, relationship to cardiovascular diseases, preclinical evidence for causality, and implications for risk prediction and mitigation.
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http://dx.doi.org/10.1016/j.jacc.2019.05.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662618PMC
July 2019

Potential Therapeutic Value of Interleukin 1b-targeted Strategies in Atherosclerotic Cardiovascular Disease.

Rev Esp Cardiol (Engl Ed) 2019 Sep 9;72(9):760-766. Epub 2019 May 9.

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Electronic address:

Clinical trials have unequivocally shown that cholesterol-lowering drugs decrease the risk of atherosclerotic cardiovascular disease in an exceptionally wide range of individuals. Yet, even when treated optimally according to current standards, many individuals still experience life-threatening ischemic events. Emerging experimental and clinical evidence strongly suggests that persistent inflammation is a major driver of this residual risk, which has opened the door to the application of anti-inflammatory drugs for cardiovascular disease prevention. Here, we review our current knowledge of the biology of interleukin-1β, a key regulator of inflammation in atherosclerotic plaque and the target of the first clinical trial to demonstrate that an anti-inflammatory drug can effectively reduce cardiovascular risk. We discuss the challenges faced by interleukin-1β inhibitors and other anti-inflammatory compounds in their translation to the clinical scenario, and identify other potential targets within this signaling pathway that hold promise in the cardiovascular setting.
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http://dx.doi.org/10.1016/j.rec.2019.03.006DOI Listing
September 2019

Integrated Stress Response Inhibition in Atherosclerosis: Preventing the Stressed-Out Plaque.

Authors:
José J Fuster

J Am Coll Cardiol 2019 03;73(10):1170-1172

Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2019.01.015DOI Listing
March 2019

TLR4 in Atherogenesis: Paying the Toll for Antimicrobial Defense.

Authors:
José J Fuster

J Am Coll Cardiol 2018 04;71(14):1571-1573

Robert M. Berne Cardiovascular Research Center and Department of Medicine, University of Virginia School of Medicine, Charlottesville, Virginia. Electronic address:

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http://dx.doi.org/10.1016/j.jacc.2018.02.014DOI Listing
April 2018

Tet2-Mediated Clonal Hematopoiesis Accelerates Heart Failure Through a Mechanism Involving the IL-1β/NLRP3 Inflammasome.

J Am Coll Cardiol 2018 02;71(8):875-886

Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts. Electronic address:

Background: Recent studies have shown that hematopoietic stem cells can undergo clonal expansion secondary to somatic mutations in leukemia-related genes, thus leading to an age-dependent accumulation of mutant leukocytes in the blood. This somatic mutation-related clonal hematopoiesis is common in healthy older individuals, but it has been associated with an increased incidence of future cardiovascular disease. The epigenetic regulator TET2 is frequently mutated in blood cells of individuals exhibiting clonal hematopoiesis.

Objectives: This study investigated whether Tet2 mutations within hematopoietic cells can contribute to heart failure in 2 models of cardiac injury.

Methods: Heart failure was induced in mice by pressure overload, achieved by transverse aortic constriction or chronic ischemia induced by the permanent ligation of the left anterior descending artery. Competitive bone marrow transplantation strategies with Tet2-deficient cells were used to mimic TET2 mutation-driven clonal hematopoiesis. Alternatively, Tet2 was specifically ablated in myeloid cells using Cre recombinase expressed from the LysM promoter.

Results: In both experimental heart failure models, hematopoietic or myeloid Tet2 deficiency worsened cardiac remodeling and function, in parallel with increased interleukin-1beta (IL-1β) expression. Treatment with a selective NLRP3 inflammasome inhibitor protected against the development of heart failure and eliminated the differences in cardiac parameters between Tet2-deficient and wild-type mice.

Conclusions: Tet2 deficiency in hematopoietic cells is associated with greater cardiac dysfunction in murine models of heart failure as a result of elevated IL-1β signaling. These data suggest that individuals with TET2-mediated clonal hematopoiesis may be at greater risk of developing heart failure and respond better to IL-1β-NLRP3 inflammasome inhibition.
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http://dx.doi.org/10.1016/j.jacc.2017.12.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828038PMC
February 2018

Somatic Mutations and Clonal Hematopoiesis: Unexpected Potential New Drivers of Age-Related Cardiovascular Disease.

Circ Res 2018 02;122(3):523-532

From the Molecular Cardiology Unit, Whitaker Cardiovascular Institute, Boston University School of Medicine, MA.

Increasing evidence shows that conventional cardiovascular risk factors are incompletely predictive of cardiovascular disease, particularly in elderly individuals, suggesting that there may still be unidentified causal risk factors. Although the accumulation of somatic DNA mutations is a hallmark of aging, its relevance in cardiovascular disease or other age-related conditions has been, with the exception of cancer, largely unexplored. Here, we review recent clinical and preclinical studies that have identified acquired mutations in hematopoietic stem cells and subsequent clonal hematopoiesis as a new cardiovascular risk factor and a potential major driver of atherosclerosis. Understanding the mechanisms underlying the connection between somatic mutation-driven clonal hematopoiesis and cardiovascular disease will be highly relevant in the context of personalized medicine, as it may provide key information for the design of diagnostic, preventive, or therapeutic strategies tailored to the effects of specific somatic mutations.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.312115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5826570PMC
February 2018

Defective p27 phosphorylation at serine 10 affects vascular reactivity and increases abdominal aortic aneurysm development via Cox-2 activation.

J Mol Cell Cardiol 2018 03 3;116:5-15. Epub 2018 Feb 3.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBER-CV), Spain. Electronic address:

Phosphorylation at serine 10 (S10) is the major posttranslational modification of the tumor suppressor p27, and is reduced in both human and mouse atherosclerosis. Moreover, a lack of p27-phospho-S10 in apolipoprotein E-null mice (apoE-/-) leads to increased high-fat diet-induced atherosclerosis associated with endothelial dysfunction and augmented leukocyte recruitment. In this study, we analyzed whether p27-phospho-S10 modulates additional endothelial functions and associated pathologies. Defective p27-phospho-S10 increases COX-2 activity in mouse aortic endothelial cells without affecting other key regulators of vascular reactivity, reduces endothelium-dependent dilation, and increases arterial contractility. Lack of p27-phospho-S10 also elevates aortic COX-2 expression and thromboxane A production, increases aortic lumen diameter, and aggravates angiotensin II-induced abdominal aortic aneurysm development in apoE-/- mice. All these abnormal responses linked to defective p27-phospho-S10 are blunted by pharmacological inhibition of COX-2. These results demonstrate that defective p27-phospho-S10 modifies endothelial behavior and promotes aneurysm formation via COX-2 activation.
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http://dx.doi.org/10.1016/j.yjmcc.2018.01.010DOI Listing
March 2018

Activation of non-canonical WNT signaling in human visceral adipose tissue contributes to local and systemic inflammation.

Sci Rep 2017 12 11;7(1):17326. Epub 2017 Dec 11.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 715 Albany Street, W-611, Boston, MA, USA.

The accumulation of visceral adiposity is strongly associated with systemic inflammation and increased cardiometabolic risk. WNT5A, a non-canonical WNT ligand, has been shown to promote adipose tissue inflammation and insulin resistance in animal studies. Among other non-canonical pathways, WNT5A activates planar cell polarity (PCP) signaling. The current study investigated the potential contribution of non-canonical WNT5A/PCP signaling to visceral adipose tissue (VAT) inflammation and associated metabolic dysfunction in individuals with obesity. VAT and subcutaneous adipose tissue (SAT) samples obtained from subjects undergoing bariatric surgery were analyzed by qRT-PCR for expression of WNT/PCP genes. In vitro experiments were conducted with preadipocytes isolated from VAT and SAT biopsies. The expression of 23 out of 33 PCP genes was enriched in VAT compared to SAT. Strong positive expression correlations of individual PCP genes were observed in VAT. WNT5A expression in VAT, but not in SAT, correlated with indexes of JNK signaling activity, IL6, waist-to-hip ratio and hsCRP. In vitro, WNT5A promoted the expression of IL6 in human preadipocytes. In conclusion, elevated non-canonical WNT5A signaling in VAT contributes to the exacerbated IL-6 production in this depot and the low-grade systemic inflammation typically associated with visceral adiposity.
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http://dx.doi.org/10.1038/s41598-017-17509-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725530PMC
December 2017

Genetic deficiency of Wnt5a diminishes disease severity in a murine model of rheumatoid arthritis.

Arthritis Res Ther 2017 07 19;19(1):166. Epub 2017 Jul 19.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany Street, W-611, Boston, MA, 02118, USA.

Background: Rheumatoid arthritis (RA) is a common autoimmune disease characterized by chronic inflammation of the joints, leading to bone erosion and joint dysfunction. Despite the recent successes of disease-modifying anti-rheumatic drugs (DMARDs), there is still clinical need for understanding the development and molecular etiology of RA. Wnts are developmental morphogens whose roles in adult pathology are poorly characterized. Wnt5a is a member of the non-canonical family of Wnts that modulates a wide range of cell processes, including differentiation, migration, and inflammation. Wnt5a has been implicated as a possible contributor to arthritis and it is upregulated in synovial fibroblasts from RA patients.

Methods: We investigated the role of endogenous Wnt5a in RA. Tamoxifen-inducible, Wnt5a knockout (Wnt5a cKO) mice and littermate controls were monitored for arthritis development and joint pathology using the K/BxN serum transfer-induced arthritis (STIA) model. To explore a role of Wnt5a in osteoclast fusion, bone marrow-derived monocytes (BMDMs) were differentiated in vitro.

Results: Wnt5a cKO mice were resistant to arthritis development compared to control littermates as assessed by ankle thickness and histologic measurements. Some parameters of inflammation were reduced in the Wnt5a cKO mice, including the extent of polymononuclear cell infiltration and extra-articular inflammation. Wnt5a cKO mice also exhibited less cartilage destruction and a reduction in osteoclast activity with concomitant reduction in tartrate-resistant acid phosphatase (TRAP), cathepsin K (CTSK), macrophage colony-stimulating factor (MCSF), matrix metalloproteinase (MMP)2 and MMP9 in the arthritic joints. Treatment of BMDMs with Wnt5a enhanced osteoclast fusion and increased the expression of dendrocyte-expressed seven transmembrane protein (DCSTAMP) and MMP9, that are necessary for osteoclast formation and activity.

Conclusions: These data suggest that Wnt5a modulates the development of arthritis by promoting inflammation and osteoclast fusion, and provide the first mouse genetic evidence of a role for endogenous Wnt5a in autoimmune disease.
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http://dx.doi.org/10.1186/s13075-017-1375-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518154PMC
July 2017

Humans and Mice Display Opposing Patterns of "Browning" Gene Expression in Visceral and Subcutaneous White Adipose Tissue Depots.

Front Cardiovasc Med 2017 5;4:27. Epub 2017 May 5.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.

Visceral adiposity is much more strongly associated with cardiometabolic disease in humans than subcutaneous adiposity. Browning, the appearance of brown-like adipocytes in the white adipose tissue (WAT), has been shown to protect mice against metabolic dysfunction, suggesting the possibility of new therapeutic approaches to treat obesity and type 2 diabetes. In mice, subcutaneous WAT depots express higher levels of browning genes when compared with visceral WAT, further suggesting that differences in WAT browning could contribute to the differences in the pathogenicity of the two depots. However, the expression of browning genes in different WAT depots of human has not been characterized. Here, it is shown that the expression of browning genes is higher in visceral than in subcutaneous WAT in humans, a pattern that is opposite to what is observed in mice. These results suggest that caution should be applied in extrapolating the results of murine browning gene expression studies to human pathophysiology.
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http://dx.doi.org/10.3389/fcvm.2017.00027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418233PMC
May 2017

Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice.

Science 2017 02 19;355(6327):842-847. Epub 2017 Jan 19.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.

Human aging is associated with an increased frequency of somatic mutations in hematopoietic cells. Several of these recurrent mutations, including those in the gene encoding the epigenetic modifier enzyme TET2, promote expansion of the mutant blood cells. This clonal hematopoiesis correlates with an increased risk of atherosclerotic cardiovascular disease. We studied the effects of the expansion of -mutant cells in atherosclerosis-prone, low-density lipoprotein receptor-deficient () mice. We found that partial bone marrow reconstitution with TET2-deficient cells was sufficient for their clonal expansion and led to a marked increase in atherosclerotic plaque size. TET2-deficient macrophages exhibited an increase in NLRP3 inflammasome-mediated interleukin-1β secretion. An NLRP3 inhibitor showed greater atheroprotective activity in chimeric mice reconstituted with TET2-deficient cells than in nonchimeric mice. These results support the hypothesis that somatic mutations in blood cells play a causal role in atherosclerosis.
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http://dx.doi.org/10.1126/science.aag1381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542057PMC
February 2017

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

Vasc Med 2016 12 28;21(6):489-496. Epub 2016 Sep 28.

Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m) and five metabolically normal non-obese (BMI 26±2 kg/m) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease.
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http://dx.doi.org/10.1177/1358863X16666693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491334PMC
December 2016

Obesity-Induced Changes in Adipose Tissue Microenvironment and Their Impact on Cardiovascular Disease.

Circ Res 2016 May;118(11):1786-807

From the Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA (J.J.F., N.G., K.W.); and Department of Molecular Cardiology, Nagoya University School of Medicine, Nagoya, Japan (N.O.).

Obesity is causally linked with the development of cardiovascular disorders. Accumulating evidence indicates that cardiovascular disease is the collateral damage of obesity-driven adipose tissue dysfunction that promotes a chronic inflammatory state within the organism. Adipose tissues secrete bioactive substances, referred to as adipokines, which largely function as modulators of inflammation. The microenvironment of adipose tissue will affect the adipokine secretome, having actions on remote tissues. Obesity typically leads to the upregulation of proinflammatory adipokines and the downregulation of anti-inflammatory adipokines, thereby contributing to the pathogenesis of cardiovascular diseases. In this review, we focus on the microenvironment of adipose tissue and how it influences cardiovascular disorders, including atherosclerosis and ischemic heart diseases, through the systemic actions of adipokines.
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http://dx.doi.org/10.1161/CIRCRESAHA.115.306885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4887147PMC
May 2016

Endothelial Dysfunction in Human Diabetes Is Mediated by Wnt5a-JNK Signaling.

Arterioscler Thromb Vasc Biol 2016 Mar 21;36(3):561-9. Epub 2016 Jan 21.

From the Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, MA.

Objective: Endothelial dysfunction is linked to insulin resistance, inflammatory activation, and increased cardiovascular risk in diabetes mellitus; however, the mechanisms remain incompletely understood. Recent studies have identified proinflammatory signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a regulator of metabolic dysfunction with potential relevance to vascular function. We sought to gain evidence that increased activation of Wnt5a-JNK signaling contributes to impaired endothelial function in patients with diabetes mellitus.

Approach And Results: We measured flow-mediated dilation of the brachial artery and characterized freshly isolated endothelial cells by protein expression, eNOS activation, and nitric oxide production in 85 subjects with type 2 diabetes mellitus (n=42) and age- and sex-matched nondiabetic controls (n=43) and in human aortic endothelial cells treated with Wnt5a. Endothelial cells from patients with diabetes mellitus displayed 1.3-fold higher Wnt5a levels (P=0.01) along with 1.4-fold higher JNK activation (P<0.01) without a difference in total JNK levels. Higher JNK activation was associated with lower flow-mediated dilation, consistent with endothelial dysfunction (r=0.53, P=0.02). Inhibition of Wnt5a and JNK signaling restored insulin and A23187-mediated eNOS activation and improved nitric oxide production in endothelial cells from patients with diabetes mellitus. In endothelial cells from nondiabetic controls, rWnt5a treatment inhibited eNOS activation replicating the diabetic endothelial phenotype. In human aortic endothelial cells, Wnt5a-induced impairment of eNOS activation and nitric oxide production was reversed by Wnt5a and JNK inhibition.

Conclusions: Our findings demonstrate that noncanonical Wnt5a signaling and JNK activity contribute to vascular insulin resistance and endothelial dysfunction and may represent a novel therapeutic opportunity to protect the vasculature in patients with diabetes mellitus.
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http://dx.doi.org/10.1161/ATVBAHA.115.306578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4913891PMC
March 2016

Heart Failure With Preserved Ejection Fraction Induces Beiging in Adipose Tissue.

Circ Heart Fail 2016 Jan;9(1):e002724

From the Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (M.V.-M., S.L., R.M.W., T.A., J.J.F., F.S.); Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston (M.H., M.N.); Departments of Internal Medicine and Cell Biology, Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas (P.E.S.); and Cardiovascular Section (F.S.) and Evans Department of Internal Medicine (T.A., F.S.), Boston University School of Medicine, MA.

Background: Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there are no evidence-based therapies for HFpEF. Clinical studies suggest a relationship between obesity-associated dysfunctional adipose tissue (AT) and HFpEF. However, an apparent obesity paradox exists in some HF populations with a higher body mass index. We sought to determine whether HFpEF exerted effects on AT and investigated the involved mechanisms.

Methods And Results: Mice underwent d-aldosterone infusion, uninephrectomy, and were given 1% saline for 4 weeks. HFpEF mice developed hypertension, left ventricular hypertrophy, and diastolic dysfunction and had higher myocardial natriuretic peptide expression. Although body weights were similar in HFpEF and sham-operated mice, white AT was significantly smaller in HFpEF than in sham (epididymal AT, 7.59 versus 10.67 mg/g; inguinal AT, 6.34 versus 8.38 mg/g). These changes were associated with smaller adipocyte size and increased beiging markers (ucp-1, cidea, and eva) in white AT. Similar findings were seen in HFpEF induced by transverse aortic constriction. Increased activation of natriuretic peptide signaling was seen in white AT of HFpEF mice. The ratio of the signaling receptor, natriuretic peptide receptor type A, to the clearance receptor, nprc, was increased as was p38 mitogen-activated protein kinase activation. However, HFpEF mice failed to regulate body temperature during cold temperature exposure. In HFpEF, despite a larger brown AT mass (5.96 versus 4.50 mg/g), brown AT showed reduced activity with decreased uncoupling protein 1 (ucp-1), cell death-inducing DFFA-like effector a (cidea), and epithelial V-like antigen (eva) expression and decreased expression of lipolytic enzymes (hormone-sensitive lipase, lipoprotein lipase, and fatty acid binding protein 4) versus sham.

Conclusions: These findings show that HFpEF is associated with beiging in white AT and with dysfunctional brown AT.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.115.002724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698901PMC
January 2016

Secreted Frizzled-related Protein 5 Diminishes Cardiac Inflammation and Protects the Heart from Ischemia/Reperfusion Injury.

J Biol Chem 2016 Feb 2;291(6):2566-75. Epub 2015 Dec 2.

From the Whitaker Cardiovascular Institute, Boston University Medical Campus, Boston, Massachusetts 02118 and

Wnt signaling has diverse actions in cardiovascular development and disease processes. Secreted frizzled-related protein 5 (Sfrp5) has been shown to function as an extracellular inhibitor of non-canonical Wnt signaling that is expressed at relatively high levels in white adipose tissue. The aim of this study was to investigate the role of Sfrp5 in the heart under ischemic stress. Sfrp5 KO and WT mice were subjected to ischemia/reperfusion (I/R). Although Sfrp5-KO mice exhibited no detectable phenotype when compared with WT control at baseline, they displayed larger infarct sizes, enhanced cardiac myocyte apoptosis, and diminished cardiac function following I/R. The ischemic lesions of Sfrp5-KO mice had greater infiltration of Wnt5a-positive macrophages and greater inflammatory cytokine and chemokine gene expression when compared with WT mice. In bone marrow-derived macrophages, Wnt5a promoted JNK activation and increased inflammatory gene expression, whereas treatment with Sfrp5 blocked these effects. These results indicate that Sfrp5 functions to antagonize inflammatory responses after I/R in the heart, possibly through a mechanism involving non-canonical Wnt5a/JNK signaling.
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http://dx.doi.org/10.1074/jbc.M115.693937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742726PMC
February 2016

Quantification of Cellular Proliferation in Mouse Atherosclerotic Lesions.

Authors:
José J Fuster

Methods Mol Biol 2015 ;1339:201-10

Whitaker Cardiovascular Institute, Boston University School of Medicine, 700 Albany Street, W-611, Boston, MA, USA.

Excessive cell proliferation within atherosclerotic plaques plays an important role in the progression of atherosclerosis. Macrophage proliferation in particular has become a major focus of attention in the cardiovascular field because it appears to mediate most of macrophage expansion in mouse atherosclerotic arteries. Therefore, quantification of cell proliferation is an essential part of the characterization of atherosclerotic plaques in experimental studies. This chapter describes two variants of a simple immunostaining protocol that allow for the quantification of cellular proliferation in mouse atherosclerotic lesions based on the detection of the proliferation-associated antigen Ki-67.
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http://dx.doi.org/10.1007/978-1-4939-2929-0_14DOI Listing
April 2016

Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion.

Diabetes 2015 Apr 28;64(4):1235-48. Epub 2014 Oct 28.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA

Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion.
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http://dx.doi.org/10.2337/db14-1164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4375084PMC
April 2015

The good, the bad, and the ugly of interleukin-6 signaling.

EMBO J 2014 Jul 21;33(13):1425-7. Epub 2014 May 21.

Molecular Cardiology, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.

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http://dx.doi.org/10.15252/embj.201488856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194086PMC
July 2014

Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization.

J Biol Chem 2014 Mar 30;289(12):8633-44. Epub 2014 Jan 30.

From the Vascular Biology Section and.

Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes, and Glrx overexpression inhibits VEGF-induced EC migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx-overexpressing EC from Glrx transgenic (TG) mice showed impaired migration and network formation and secreted higher levels of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared with wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Noncanonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC and enhanced NF-κB activity, which was responsible for Wnt5a-sFlt induction. Taken together, up-regulated Glrx induces sFlt in EC via NF-κB-dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt explains part of the mechanism of redox-regulated VEGF signaling.
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http://dx.doi.org/10.1074/jbc.M113.517219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961686PMC
March 2014

Adipokines: a link between obesity and cardiovascular disease.

J Cardiol 2014 Apr 16;63(4):250-9. Epub 2013 Dec 16.

Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA. Electronic address:

Obesity is a risk factor for various cardiovascular diseases including hypertension, atherosclerosis, and myocardial infarction. Recent studies aimed at understanding the microenvironment of adipose tissue and its impact on systemic metabolism have shed light on the pathogenesis of obesity-linked cardiovascular diseases. Adipose tissue functions as an endocrine organ by secreting multiple immune-modulatory proteins known as adipokines. Obesity leads to increased expression of pro-inflammatory adipokines and diminished expression of anti-inflammatory adipokines, resulting in the development of a chronic, low-grade inflammatory state. This adipokine imbalance is thought to be a key event in promoting both systemic metabolic dysfunction and cardiovascular disease. This review will focus on the adipose tissue microenvironment and the role of adipokines in modulating systemic inflammatory responses that contribute to cardiovascular disease.
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http://dx.doi.org/10.1016/j.jjcc.2013.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3989503PMC
April 2014

PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions.

PLoS One 2013 22;8(8):e72674. Epub 2013 Aug 22.

Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB-CSIC), Madrid, Spain.

Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110γ in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110γ(+/-) and LDLR(-/-)p110γ(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110γ(+/-) and p110γ(-/-) mice. Lack of p110γ in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110γ(-/-) mice were smaller than in LDLR(-/-)p110γ(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110γ(-/-) mouse lesions. This proliferation defect was also observed in p110γ(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110γ(-/-) mice. Moreover, p110γ deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR(-/-) mice lacking p110γ. Nonetheless, p110γ deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0072674PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750002PMC
June 2014

Increased gene dosage of the Ink4/Arf locus does not attenuate atherosclerosis development in hypercholesterolaemic mice.

Atherosclerosis 2012 Mar 17;221(1):98-105. Epub 2011 Dec 17.

Department of Epidemiology, Atherothrombosis and Imaging, Centro Nacional de Investigaciones Cardiovasculares, Melchor Fernández Almagro 3, 28029 Madrid, Spain.

Rationale: Human genome-wide association studies have identified genetic variants in the chromosome 9p21 region that confer increased risk of coronary artery disease and other age-related diseases. These variants are located in a block of high linkage disequilibrium with the neighboring Ink4/Arf tumor-suppressor locus (also named CDKN2A/CDKN2B). Since previous studies suggest an atheroprotective role of the Ink4/Arf locus, here we assessed whether gain-of-function of the encoded genes can be exploited therapeutically to reduce atherosclerosis.

Methods: Generation and characterization of apolipoprotein E-null mice carrying an additional transgenic copy of the entire Ink4/Arf locus (apoE-/-Super-Ink4/Arf) that reproduces the normal expression and regulation of the endogenous locus.

Results: Although liver and aorta of apoE-/-Super-Ink4/Arf mice only showed a trend towards increased Ink4/Arf transcript levels compared to apoE-/- controls, cultured macrophages with increased Ink4/Arf gene dosage exhibited augmented apoptosis induced by irradiation with ultraviolet light, indicating that low level of transgene overexpression can lead to augmented Ink4/Arf function. However, increased Ink4/Arf gene dosage did not affect atherosclerosis development in different vascular regions of both male and female apoE-/- mice fed either normal or high-fat diet. Increased gene dosage of Ink4/Arf similarly had no effect on atheroma cell composition or collagen content, an index of plaque stability.

Conclusion: In contrast with previous studies demonstrating cancer resistance in Super-Ink4/Arf mice carrying an additional transgenic copy of the entire Ink4/Arf locus, our results cast doubt on the potential of Ink4/Arf activation as a strategy for the treatment of atherosclerotic disease.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.12.013DOI Listing
March 2012
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