Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy

doi:10.1016/j.carpath.2010.03.007

Cardiovascular Pathology

Volume 20, Issue 2, March–April 2011, Pages e57-e68

https://doi.org/10.1016/j.carpath.2010.03.007 Get rights and content

Abstract

Introduction

Previously, we demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) exerts protective effects against high-fat (HF) diet-induced atherogenesis in part by increasing tissue inhibitor of metalloproteinase (TIMP)-2 expression. Given that characteristics of dilated cardiomyopathy closely associate with atherosclerosis and are mediated by an imbalance between matrix metalloproteinases (MMPs) and TIMPs, we hypothesized that PARP-1 gene deletion may protect against HF-induced cardiac hypertrophy and dilatations by altering TIMP-2/MMPs balance in favor of a maintenance of tissue homeostasis.

Methods and results

Hemodynamic parameters determined by echocardiography were similar in ApoE^−/− mice and PARP-1-deficient ApoE^−/− mice (DKO) fed a regular diet (RD). However, histological analysis revealed that cardiomyocytes of ApoE^−/− mice on RD were hypertrophied, displaying an enlarged cell body and nucleus, traits that were absent in DKO animals. HF diet-fed ApoE^−/− mice exhibited increased interventricular septum, left ventricular (LV) internal dimension, LV volume, and LV mass in addition to a separation of myocardial fibers suggestive of dilated cardiomyopathy. PARP-1 gene deletion protected against these degenerative changes. MMP activity was dramatically increased in hearts of ApoE^−/− mice on HF diet and was accompanied by increased collagen degradation, mast cell degranulation, and increased myocyte cell death. PARP-1 gene knockout was associated with increased TIMP-2 expression antagonizing, as a result, the damaging effects of active MMPs.

Conclusions

The present study demonstrates that PARP-1 gene deletion exerts protective effects against HF diet-induced dilated cardiomyopathy by maintaining increased expression of TIMP-2. With additional protective effects against cell death and inflammation, PARP-1 deficiency preserves cardiac tissue homeostasis.

Introduction

Cardiac hypertrophy starts as an adaptive response of the heart against hemodynamic overload induced by stress and/or other physiological factors such as exercise [1], [2]. The deleterious progression of cardiac hypertrophy to dilatations and ultimately heart failure is very complex and involves activation of numerous secondary pathways including activation of matrix metalloproteinases (MMPs), TNF, signaling, and apoptotic pathways, as well as activation of poly(ADP-ribose) polymerase (PARP) [3], [4], [5], [6].

PARP-1 is a major member of the PARP protein family, whose function has been classically associated with sensing DNA lesions in response to DNA damaging agents [7]. Oxidative and nitrosative stress triggers the activation of PARP, which contributes to the pathogenesis of various cardiovascular diseases [8], [9], [10], [11]. Because of its active participation in chronic inflammation, PARP has been suggested to play an active role in progression of atherosclerotic plaques [8], [9], [10], [11], [12]. In previous studies, we reported that PARP inhibition provides stability to atherosclerotic plaques which was associated with increased expression of tissue inhibitor of MMPs (TIMP)-2 and decreased extracellular matrix (ECM) degradation [9].

An optimal balance between TIMPs and MMPs is required for the maintenance and tight regulation of the dynamic ECM environment. An alteration in such delicate balance may constitute a critical contributing factor to various cardiovascular disease states such as hypertension, atherosclerosis, aortic aneurysm, and cardiac hypertrophy [13]. Clinical as well as experimental studies have shown a strong correlation between MMP activity and manifestation of heart diseases [3], [14]. In fact, myocardial matrix degradation and activation of MMPs in the failing heart have been suggested as viable therapeutic targets [3], [15]. Cardiac hypertrophy is a potent risk factor for the development of cardiac arrhythmias, diastolic dysfunction, congestive heart failure, and death.

Since atherosclerosis and cardiac dysfunctions are so closely related, we hypothesized that PARP-1 gene deletion may protect against cardiac dysfunctions mediated by high-fat (HF) diet-associated dyslipidemia and associated inflammation. Thus, we examined the effects of PARP-1 gene deletion on HF diet-induced cardiac functions and correlated the observed hemodynamic parameters with histopathological changes. We also investigated the protective effects of PARP-1 gene deletion on MMP activity, collagen degradation, and tissue integrity (apoptotic cell death).

Section snippets

Generation of ApoE^−/−–PARP-1^−/− double knockout mice

C57BL/6 [wild type (WT)], ApoE^−/− (The Jackson Laboratory, Bar Harbor, ME, USA), PARP-1^−/−, and ApoE^−/−–PARP-1^−/− double knockout (DKO) mice were housed and bred in a pathogen-free animal care facility at LSUHSC, New Orleans, LA, and allowed full access to laboratory rodent chow and water. Experimental protocols were approved by the LSUHSC Animal Care and Use Committee. The generation of the C57BL/6 PARP-1^−/− mice has been previously described [9]. DKO mice were generated by breeding ApoE^−/−

PARP-1 gene deletion protected against cardiac dysfunction: hemodynamic parameter analysis

Cardiac hemodynamic parameters as measured by echocardiography are summarized in Table 1, Table 2. There was no significant difference in the hemodynamic parameters in ApoE^−/− mice and PARP-1-deficient ApoE^−/− mice (DKO) on regular diet (RD). After 8 weeks on HF diet, there were evidences of left ventricular (LV) hypertrophy and dilatations in ApoE^−/− vs. DKO as suggested by parameters including diastolic IVS (0.72±0.1 vs. 0.61±0.03), LV internal dimension in diastole (4.57±0.35 vs. 3.68±0.38),

Discussion

Cardiac hypertrophy is closely related to atherosclerosis and is considered a disease of ECM imbalance. We hypothesized a protective effect of PARP-1 gene deletion on cardiac hypertrophy in the mouse model of atherosclerosis. HF diet regimen caused cardiac hypertrophy and dilatation of the heart of ApoE^−/− mice which was found to be associated with increased MMP-9 activity in heart, degranulation of mast cells, and increased caspase-3-dependent apoptotic cell death. These traits are closely

Acknowledgments

We thank Dr. Yves A. DeClerck (The Saban Research Institute, Division of Hematology/Oncology, Children's Hospital of Los Angeles, Los Angeles, CA, USA) for providing us the TIMP-2 construct. We also thank Elizabeth McIlwain for echocardiography analysis and Dr. William Claycomb for providing the HL-1 cardiomyocytes.

References (41)

CarrenoJE et al.
Cardiac hypertrophy: molecular and cellular events
Rev Esp Cardiol
(2006)
ChalmersAJ
Poly(ADP-ribose) polymerase-1 and ionizing radiation: sensor, signaller and therapeutic target
Clin Oncol (R Coll Radiol)
(2004)
HammaniK et al.
Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene
J Biol Chem
(1996)
ZhongZD et al.
NF-Y and Sp1 cooperate for the transcriptional activation and cAMP response of human tissue inhibitor of metalloproteinases-2
J Biol Chem
(2000)
MurakamiS et al.
Improvement in cholesterol metabolism in mice given chronic treatment of taurine and fed a high-fat diet
Life Sci
(1998)
WangYX
Cardiovascular functional phenotypes and pharmacological responses in apolipoprotein E deficient mice
Neurobiol Aging
(2005)
Stetler-StevensonWG et al.
TIMP-2: an endogenous inhibitor of angiogenesis
Trends Mol Med
(2005)
SeoD-W et al.
TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism
Cell
(2003)
CuzzocreaS
Shock, inflammation and PARP
Pharmacol Res
(2005)
GuptaS et al.
Cardiac hypertrophy: mechanisms and therapeutic opportunities
Antioxid Redox Signal
(2007)

SpinaleFG

Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function

Physiol Rev

(2007)

HaudekSB et al.

TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways

J Clin Invest

(2007)

PillaiJB et al.

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Am J Physiol Heart Circ Physiol

(2006)

BalakumarP et al.

Possible role of poly(ADP-ribose) polymerase in pathological and physiological cardiac hypertrophy

Methods Find Exp Clin Pharmacol

(2006)

HansCP et al.

Protective effects of PARP-1 knockout on dyslipidemia-induced autonomic and vascular dysfunction in ApoE mice: effects on eNOS and oxidative stress

PLoS One

(2009)

Oumouna-BenachourK et al.

Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death

Circulation

(2007)

PacherP et al.

Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors

Cardiovasc Drug Rev

(2007)

HansCP et al.

Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability

Cardiovasc Res

(2008)

von LukowiczT et al.

PARP1 is required for adhesion molecule expression in atherogenesis

Cardiovasc Res

(2008)

ZervoudakiA et al.

Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment

J Hum Hypertens

(2003)

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Genetic or pharmacological inhibition of PARP enzymes have beneficial effects in hyperlipidemia of different etiology as diabetes, high-fat feeding or high cholesterol feeding (Table 3). Most results point out that the inhibition of PARP1 or tankyrases reduce serum total cholesterol levels [101,260–262] and improve the HDL/LDL ratio [101,260–262]. The promoter of apolipoprotein D, a constituent of HDL, was shown to be positively regulated in NIH 3 T3 fibroblasts by PARP1 [263].
PARPs and tankyrases (TNKS) represent a family of 17 proteins. PARPs and tankyrases were originally identified as DNA repair factors, nevertheless, recent advances have shed light on their role in lipid metabolism. To date, PARP1, PARP2, PARP3, tankyrases, PARP9, PARP10, PARP14 were reported to have multi-pronged connections to lipid metabolism. The activity of PARP enzymes is fine-tuned by a set of cholesterol-based compounds as oxidized cholesterol derivatives, steroid hormones or bile acids. In turn, PARPs modulate several key processes of lipid homeostasis (lipotoxicity, fatty acid and steroid biosynthesis, lipoprotein homeostasis, fatty acid oxidation, etc.). PARPs are also cofactors of lipid-responsive nuclear receptors and transcription factors through which PARPs regulate lipid metabolism and lipid homeostasis. PARP activation often represents a disruptive signal to (lipid) metabolism, and PARP-dependent changes to lipid metabolism have pathophysiological role in the development of hyperlipidemia, obesity, alcoholic and non-alcoholic fatty liver disease, type II diabetes and its complications, atherosclerosis, cardiovascular aging and skin pathologies, just to name a few. In this synopsis we will review the evidence supporting the beneficial effects of pharmacological PARP inhibitors in these diseases/pathologies and propose repurposing PARP inhibitors already available for the treatment of various malignancies.
Novel biomarkers in the prognosis of patients with atherosclerotic coronary artery disease
2020, Revista Portuguesa de Cardiologia
Biomarkers have a variety of clinical applications in multiple stages of diagnosis and therapy. Troponin T and brain natriuretic peptide are the best-known in the cardiovascular field, but experimental studies have identified new biomarkers with potential clinical value. In this article, novel biomarkers of kidney injury are investigated in the context of their relationship with atherosclerotic coronary disease. This review was carried out through a search in the PubMed database using as keywords each biomarker to be studied with the descriptor (DECS/MeSH) “Myocardial Infarction”, and the keywords “coronary” and “cardiovascular”, using the Boolean operator “AND”. After the selection, 24 articles published between 2003 and 2017 were identified for the review. Eight biomarkers were investigated: neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor 23 (FGF23), tissue inhibitor of metalloproteinase-2 (TIMP-2), syndecan-1, interleukin-6 (IL-6), galectin-3, and the vascular cell adhesion molecules ICAM-1 and VCAM-1. Most identified articles were experimental studies, studies on human subjects having few participants. There are several promising biomarkers in the setting of coronary disease. The main evidence available in the literature suggests that elevated NGAL levels are associated with better prognosis after cardiac arrest and with comorbid kidney injury; elevated FGF23 is associated with coronary artery disease severity; TIMP-2 protects against coronary artery disease; increased expression of syndecan-1 is observed in myocardial infarction (MI) and protects against an exacerbated inflammatory response; IL-6 is associated with atherosclerotic disease and major cardiovascular outcomes; galectin-3 correlates with adverse clinical events post-MI; and elevated ICAM-1/VCAM-1 levels are associated with risk of coronary disease. Further studies are required to better investigate the role of each of these biomarkers in both stable coronary disease and acute coronary syndrome.
Os biomarcadores têm uma variedade de aplicações clínicas em vários estágios do diagnóstico e terapêutica. A troponina T e o peptídeo natriurético cerebral são os mais conhecidos no campo cardiovascular, mas estudos experimentais mostraram novos biomarcadores com potencial de uso clínico. Em nosso artigo, os novos biomarcadores de lesão renal foram investigados no contexto de sua relação com doença coronariana aterosclerótica. Esta revisão foi realizada por meio de uma pesquisa no Pubmed, utilizando como palavras-chave cada biomarcador a ser estudado com o descritor (DECS/MESH): “Myocardial Infarction” e as palavras-chave “coronary” e “cardiovascular”, utilizando o Booleano operador “AND”. Após a seleção, 24 artigos publicados de 2003 a 2017 foram identificados para a revisão. Oito biomarcadores foram investigados: lipoproteína associada a gelatinase de neutrófilos, fator de crescimento de fibroblastos 23 (FGF 23), inibidor tecidual de metaloproteinases 2 (TIMP-2), sindecano 1, interleucina 6 (IL-6), galectina 3 e moléculas de adesão vascular – ICAM-1 e VCAM-1. Os artigos mais verificados foram estudos experimentais e com estudos em humanos com poucos participantes. Existem vários biomarcadores promissores no cenário da doença coronariana. As principais evidências disponíveis na literatura sugerem que níveis elevados de NGAL estão associados a um melhor prognóstico após morte súbita cardíaca e lesão renal associada; níveis elevados de FGF 23 mostraram estar associados à gravidade da doença arterial coronariana; o gene TIMP-2 protege contra doença arterial coronariana; é observada uma expressão aumentada de sindecano-1 no infarto agudo do miocárdio (IAM) e protege contra uma resposta inflamatória exacerbada; a IL-6 está associada ao aumento da doença aterosclerótica e aos principais desfechos cardiovasculares; a galectina-3 se correlaciona com eventos clínicos adversos pós-IAM; e níveis elevados de ICAM/VCAM-1 estão associados ao risco de doença coronariana. Mais estudos são necessários para investigar melhor o papel de cada um desses biomarcadores na doença coronária estável e na síndrome coronariana aguda.
Analysis of mast cells and myocardial fibrosis in autopsied patients with hypertensive heart disease
2020, Revista Portuguesa de Cardiologia
Citation Excerpt :
It has also been demonstrated that the ratio of serum matrix metalloproteinase (MMP)-1 and its tissue inhibitors is altered in patients with hypertensive heart disease,47 and that patients with reduced ejection fraction due to LV chamber dilatation present changes in the distribution of collagen fibers, mainly perivascular and scar, and considerable increases in MMP-1.40 These findings are related to the results of the present study, as activated MMPs are the main mediators of myocardial remodeling, mainly through the release of tryptase, which cleaves the pro-MMP-3 precursor, activating MMP-3 which then activates MMP-1, and through the release of chymase, which activates MMP-2 and MMP-9.48–53 This remodeling appears to be critical to the progression of LV hypertrophy.
To analyze the percentage of collagen fibers and mast cell density in the left ventricular myocardium of autopsied patients with and without hypertensive heart disease.
Thirty fragments of left ventricular myocardium were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period from 1987 to 2017. Individuals were divided into two groups: those with hypertensive heart disease (HD) and those with no heart disease (ND). Subjects were also assessed according to age, gender and race (white and non-white). Collagen fibers were quantified by computed morphometry and mast cell density was assessed by immunohistochemical methods.
There were significantly more collagen fibers in the left ventricle in the HD group than in the ND group (p< 0.001). Mast cell density was significantly higher in the left ventricle of individuals with HD immunolabeled with anti-chymase and anti-tryptase antibodies (p=0.02) and also of those immunolabeled only with anti-tryptase antibodies (p=0.03). Analyzing the HD group, there was a significant positive correlation between the percentage of collagen fibers in the left ventricle and mast cell density immunolabeled by anti-chymase and anti-tryptase antibodies (p=0.04) and also mast cell density immunolabeled only with anti-tryptase antibodies (p=0.02).
Mast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.
Analisar a porcentagem de fibras colágenas e a densidade mastocitária no miocárdio ventricular esquerdo de pacientes autopsiados com e sem cardiopatia hipertensiva.
Foram obtidos 30 fragmentos do miocárdio ventricular esquerdo de indivíduos autopsiados no Hospital Clínico da Universidade Federal do Triângulo Mineiro (UFTM) em 1987-2017, agrupados em indivíduos com cardiopatia hipertensiva (HD) e sem cardiopatia (ND) e avaliados de acordo com fatores como idade, sexo (masculino e feminino) e cor (branco e não branco). A quantificação das fibras colágenas foi feita por morfometria computadorizada e a densidade mastocitária foi avaliada por métodos imuno-histoquímicos.
Houve aumento significativo das fibras colágenas no ventrículo esquerdo no grupo HD em comparação com o grupo ND (p < 0,001). Quanto à densidade mastocitária, houve aumento significativo no ventrículo esquerdo de indivíduos com HD imunomarcados por antiquimase/antitriptase (p=0,02) e também na densidade mastocitária no ventrículo esquerdo de indivíduos imunomarcados por antitriptase (p=0,03). Analisando o grupo de HD, houve uma correlação positiva e significativa entre a porcentagem de fibras colágenas no ventrículo esquerdo e a densidade mastocitária no ventrículo esquerdo imunomarcados por antiquimase/antitriptase (p=0,04) e também na densidade mastocitária no ventrículo esquerdo de indivíduos imunomarcados por antitriptase (p=0,02).
Os mastócitos estão envolvidos no desenvolvimento da cardiopatia hipertensiva, contribuem para a remodelação das fibras colágenas nessa doença.
Morphological and histopathological evaluation of autopsied patients with hypertensive cardiopathy
2019, Annals of Diagnostic Pathology
Citation Excerpt :
In the present study, we found a significant increase in the density of mast cells in the left ventricle of individuals with hypertensive heart disease. Mast cells are the main mediators of myocardial remodeling, which occurs via activation of MMPs, mainly by the release of tryptase, which cleaves the pro-MMP-3 precursor, activating MMP-3 which then activates MMP-1 and the release of chymase, activating MMP-2 and MMP-9 [30-35]. This remodeling appears to be critical to the progression of left ventricular hypertrophy.
Physiopathological processes in hypertensive heart disease are controlled by complex interactions between cardiomyocytes, extracellular matrix, microvasculature and other cells present in the myocardium.
To analyze morphological changes in hypertensive cardiopathy and to describe and compare findings in order to help clarify determinant factors.
42 fragments of the left ventricular myocardium and circumflex branch of the left coronary artery were obtained from individuals autopsied at the Clinical Hospital of the Federal University of Triângulo Mineiro (UFTM) in the period ranging from 1984 to 2018. Groups were split into individuals with hypertensive heart disease (HD) and individuals without heart disease (ND). Wall thickness was measured with a digital caliper and Computed Tomography. Quantification of collagen fibers was conducted by computerized morphometry and mast cell density was assessed by immunohistochemical methods.
There was a significant increase of heart weight in the HD group compared to the ND group, (p = 0.0002). There was a significant increase of thickness of the middle third of the free wall in the HD group compared to the ND group, (p = 0.04). There was a significant increase of collagen fibers in the left ventricle in the HD group compared to the ND group, (p < 0.0001). Concerning mast cell density, there was a significant increase in the left ventricle of individuals with HD immuno-labeled by the set anti-chymase/anti-tryptase (p < 0.0001). There was a significant increase of mast cell density in the circumflex branch of the left coronary artery of individuals with HD immuno-labeled by the set anti-chymase/anti-tryptase (p = 0.01).
Mast cells are involved in the development of hypertensive heart disease, contributing to the remodeling of collagen fibers in this disease.
PARP activity and inhibition in fetal and adult oligodendrocyte precursor cells: Effect on cell survival and differentiation
2017, Stem Cell Research
Poly (ADP-ribose) polymerase (PARP) family members are ubiquitously expressed and play a key role in cellular processes, including DNA repair and cell death/survival balance. Accordingly, PARP inhibition is an emerging pharmacological strategy for cancer and neurodegenerative diseases. Consistent evidences support the critical involvement of PARP family members in cell differentiation and phenotype maturation. In this study we used an oligodendrocyte precursor cells (OPCs) enriched system derived from fetal and adult brain to investigate the role of PARP in OPCs proliferation, survival, and differentiation. The PARP inhibitors PJ34, TIQ-A and Olaparib were used as pharmacological tools. The main results of the study are: (i) PARP mRNA expression and PARP activity are much higher in fetal than in adult-derived OPCs; (ii) the culture treatment with PARP inhibitors is cytotoxic for OPCs derived from fetal, but not from adult, brain; (iii) PARP inhibition reduces cell number, according to the inhibitory potency of the compounds; (iv) PARP inhibition effect on fetal OPCs is a slow process; (v) PARP inhibition impairs OPCs maturation into myelinating OL in fetal, but not in adult cultures, according to the inhibitory potency of the compounds. These results have implications for PARP-inhibition therapies for diseases and lesions of the central nervous system, in particular for neonatal hypoxic/ischemic encephalopathy.
Mast cells emerge as mediators of atherosclerosis: Special emphasis on IL-37 inhibition
2017, Tissue and Cell
Citation Excerpt :
Treg subsets CD4 + CD25+, Foxp3+, and T cells are important in the maintenance of peripheral tolerance (Adar et al., 2016; Morel and Turner, 2011) and are associated with atherosclerosis and diabetes. Furthermore, TH17 lymphocytes (Taleb et al., 2015) are also associated with the plaque generation, as well as CD11b+ which are immature myeloid 4 of macrophages, dendritic cells, neutrophils (Hans et al., 2011) and mast cells, but their inhibition does not reduce atherogenic inflammation (Dow-Walsh et al., 1975). However, both chymase and tryptase play a pathophysiological role in degrading lipoproteins in the intima, which represent a serious problem for the circulatory system (Languino et al., 1995).
In atherosclerosis lipoproteins stimulate the innate immune response, leading to the release of inflammatory cytokines and chemokines. Hypercholesterolemia may activate the synthesis and release of inflammatory cytokines such as IL-1, which induces TNF release in mast cells (MCs). IL-1 and IL-1 family members orchestrate a broadening list of inflammatory diseases, including atherosclerosis. MCs are implicated in the pathophysiology of several diseases including allergy and inflammation. Activated MCs, located perivascularly, contribute to inflammation in atherosclerosis by producing inflammatory cytokines. MC IL-1-activation leads to the immediate release of inflammatory chemical mediators and TNF, and late inflammatory compounds such as cytokines. MCs can be activated by exogenous cytokines, antigens, microbial products (LPS) and neurotransmitters and generate IL-1 beta, TNF and several other inflammatory cytokines/chemokines along with PGD2, leukotrienes, histamine and proteases. MCs activated with IL-1 induce selective release of IL-6 without degranulation. TNF emerges as one of the most potent inflammatory cytokines involved in the response due to LDL. Cytokines, such as IL-1, IL-6, IL-33 and TNF, are generated in the inflammatory sites by both macrophages and MCs, mediating atherosclerosis. IL-37 (IL-1 family member 7) binds IL-18Ra chain and acts by an intracellular mechanism down-regulating the expression of pro-inflammatory signals cJun, MAP kinase p38a, STAT transcription factors and p53. Blocking IL-1 with IL-37 alleviates the symptoms in patients with inflammatory diseases including arteriosclerosis. The impact of IL-37 on inflammatory cytokines mediating atherosclerosis is beneficial and protective. However, more studies are needed to better define this mechanism and the safety and tolerability of IL-37.

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: Source of funding: This work was supported by the National Heart Blood and Lung Institute at the National Institute of Health [HL072889 and 1P20RR18766 (overall PI, D. Kapusta)]; by the American Cancer Society (RSG-116608) to AHB; and by the American Heart Association Postdoctoral fellowship (0825470E) to CPH.

: Conflict of interests: None.

¹: Current address: Department of Physiology, Tulane University Medical Center, New Orleans, LA, USA.

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Original ArticleOpposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy

Abstract

Introduction

Methods and results

Conclusions

Introduction

Section snippets

Generation of ApoE−/−–PARP-1−/− double knockout mice

PARP-1 gene deletion protected against cardiac dysfunction: hemodynamic parameter analysis

Discussion

Acknowledgments

Rev Esp Cardiol

Clin Oncol (R Coll Radiol)

J Biol Chem

J Biol Chem

Life Sci

Neurobiol Aging

Trends Mol Med

Cell

Pharmacol Res

Cardiac hypertrophy: mechanisms and therapeutic opportunities

Antioxid Redox Signal

Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function

Physiol Rev

TNF provokes cardiomyocyte apoptosis and cardiac remodeling through activation of multiple cell death pathways

J Clin Invest

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Am J Physiol Heart Circ Physiol

Possible role of poly(ADP-ribose) polymerase in pathological and physiological cardiac hypertrophy

Methods Find Exp Clin Pharmacol

Protective effects of PARP-1 knockout on dyslipidemia-induced autonomic and vascular dysfunction in ApoE mice: effects on eNOS and oxidative stress

PLoS One

Poly(ADP-ribose) polymerase inhibition reduces atherosclerotic plaque size and promotes factors of plaque stability in apolipoprotein E-deficient mice: effects on macrophage recruitment, nuclear factor-kappaB nuclear translocation, and foam cell death

Circulation

Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors

Cardiovasc Drug Rev

Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability

Cardiovasc Res

PARP1 is required for adhesion molecule expression in atherogenesis

Cardiovasc Res

Plasma levels of active extracellular matrix metalloproteinases 2 and 9 in patients with essential hypertension before and after antihypertensive treatment

J Hum Hypertens

Original Article
Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy

Generation of ApoE^−/−–PARP-1^−/− double knockout mice