International Journal of Molecular Sciences

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12 pages, 5419 KiB

Open AccessArticle

Programmed Death-Ligand 2 Deficiency Exacerbates Experimental Autoimmune Myocarditis in Mice

by Siqi Li, Kazuko Tajiri, Nobuyuki Murakoshi, DongZhu Xu, Saori Yonebayashi, Yuta Okabe, Zixun Yuan, Duo Feng, Keiko Inoue, Kazuhiro Aonuma, Yuzuno Shimoda, Zoughu Song, Haruka Mori, Honglan Huang, Kazutaka Aonuma and Masaki Ieda

Int. J. Mol. Sci. 2021, 22(3), 1426; https://doi.org/10.3390/ijms22031426 - 31 Jan 2021

Cited by 12 | Viewed by 3382

Abstract

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. [...] Read more.

Programmed death ligand 2 (PD-L2) is the second ligand of programmed death 1 (PD-1) protein. In autoimmune myocarditis, the protective roles of PD-1 and its first ligand programmed death ligand 1 (PD-L1) have been well documented; however, the role of PD-L2 remains unknown. In this study, we report that PD-L2 deficiency exacerbates myocardial inflammation in mice with experimental autoimmune myocarditis (EAM). EAM was established in wild-type (WT) and PD-L2-deficient mice by immunization with murine cardiac myosin peptide. We found that PD-L2-deficient mice had more serious inflammatory infiltration in the heart and a significantly higher myocarditis severity score than WT mice. PD-L2-deficient dendritic cells (DCs) enhanced CD4⁺ T cell proliferation in the presence of T cell receptor and CD28 signaling. These data suggest that PD-L2 on DCs protects against autoreactive CD4⁺ T cell expansion and severe inflammation in mice with EAM. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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16 pages, 5449 KiB

Open AccessArticle

A New Mouse Model of Chronic Myocarditis Induced by Recombinant Bacille Calmette–Guèrin Expressing a T-Cell Epitope of Cardiac Myosin Heavy Chain-α

by Kazuko Tajiri, Kyoko Imanaka-Yoshida, Yusuke Tsujimura, Kazuhiro Matsuo, Michiaki Hiroe, Kazutaka Aonuma, Masaki Ieda and Yasuhiro Yasutomi

Int. J. Mol. Sci. 2021, 22(2), 794; https://doi.org/10.3390/ijms22020794 - 14 Jan 2021

Cited by 8 | Viewed by 3739

Abstract

Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology [...] Read more.

Dilated cardiomyopathy (DCM) is a potentially lethal disorder characterized by progressive impairment of cardiac function. Chronic myocarditis has long been hypothesized to be one of the causes of DCM. However, owing to the lack of suitable animal models of chronic myocarditis, its pathophysiology remains unclear. Here, we report a novel mouse model of chronic myocarditis induced by recombinant bacille Calmette-Guérin (rBCG) expressing a CD4⁺ T-cell epitope of cardiac myosin heavy chain-α (rBCG-MyHCα). Mice immunized with rBCG-MyHCα developed chronic myocarditis, and echocardiography revealed dilation and impaired contraction of ventricles, similar to those observed in human DCM. In the heart, CD62L⁻CD4⁺ T cells were increased and produced significant amounts of IFN-γ and IL-17 in response to cardiac myosin. Adoptive transfer of CD62L⁻CD4⁺ T cells induced myocarditis in the recipient mice, which indicated that CD62L⁻CD4⁺ T cells were the effector cells in this model. rBCG-MyHCα-infected dendritic cells produced proinflammatory cytokines and induced MyHCα-specific T-cell proliferation and Th1 and Th17 polarization. This novel chronic myocarditis mouse model may allow the identification of the central pathophysiological and immunological processes involved in the progression to DCM. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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13 pages, 3675 KiB

Open AccessArticle

Neutrophil Elastase Deficiency Ameliorates Myocardial Injury Post Myocardial Infarction in Mice

by Yukino Ogura, Kazuko Tajiri, Nobuyuki Murakoshi, DongZhu Xu, Saori Yonebayashi, Siqi Li, Yuta Okabe, Duo Feng, Yuzuno Shimoda, Zoughu Song, Haruka Mori, Zixun Yuan, Kazutaka Aonuma and Masaki Ieda

Int. J. Mol. Sci. 2021, 22(2), 722; https://doi.org/10.3390/ijms22020722 - 13 Jan 2021

Cited by 26 | Viewed by 3524

Abstract

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase [...] Read more.

Neutrophils are recruited into the heart at an early stage following a myocardial infarction (MI). These secrete several proteases, one of them being neutrophil elastase (NE), which promotes inflammatory responses in several disease models. It has been shown that there is an increase in NE activity in patients with MI; however, the role of NE in MI remains unclear. Therefore, the present study aimed to investigate the role of NE in the pathogenesis of MI in mice. NE expression peaked on day 1 in the infarcted hearts. In addition, NE deficiency improved survival and cardiac function post-MI, limiting fibrosis in the noninfarcted myocardium. Sivelestat, an NE inhibitor, also improved survival and cardiac function post-MI. Flow cytometric analysis showed that the numbers of heart-infiltrating neutrophils and inflammatory macrophages (CD11b⁺F4/80⁺CD206^low cells) were significantly lower in NE-deficient mice than in wild-type (WT) mice. At the border zone between intact and necrotic areas, the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells was lower in NE-deficient mice than in WT mice. Western blot analyses revealed that the expression levels of insulin receptor substrate 1 and phosphorylation of Akt were significantly upregulated in NE-knockout mouse hearts, indicating that NE deficiency might improve cardiac survival by upregulating insulin/Akt signaling post-MI. Thus, NE may enhance myocardial injury by inducing an excessive inflammatory response and suppressing Akt signaling in cardiomyocytes. Inhibition of NE might serve as a novel therapeutic target in the treatment of MI. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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18 pages, 2285 KiB

Open AccessArticle

Early Pro-Inflammatory Remodeling of HDL Proteome in a Model of Diet-Induced Obesity: ²H₂O-Metabolic Labeling-Based Kinetic Approach

by Prabodh Sadana, Li Lin, Mirjavid Aghayev, Serguei Ilchenko and Takhar Kasumov

Int. J. Mol. Sci. 2020, 21(20), 7472; https://doi.org/10.3390/ijms21207472 - 10 Oct 2020

Cited by 9 | Viewed by 2529

Abstract

Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course [...] Read more.

Mice fed a high-fat diet for 12 weeks or longer develop hyperglycemia, insulin resistance, dyslipidemia, and fatty liver. Additionally, a high-fat diet induces inflammation that remodels and affects the anti-inflammatory and antiatherogenic property of the high-density lipoprotein (HDL). However, the precise time course of metabolic disease progression and HDL remodeling remains unclear. Short-term (four weeks) high-fat feeding (60% fat calories) was performed in wild-type male C57BL/6J mice to gain insights into the early metabolic disease processes in conjunction with a HDL proteome dynamics analysis using a heavy water metabolic labeling approach. The high-fat diet-fed mice developed hyperglycemia, impaired glucose tolerance, hypercholesterolemia without hypertriglyceridemia or hepatic steatosis. A plasma HDL proteome dynamics analysis revealed increased turnover rates (and reduced half-lives) of several acute-phase response proteins involved in innate immunity, including complement C3 (12.77 ± 0.81 vs. 9.98 ± 1.20 h, p < 0.005), complement factor B (12.71 ± 1.01 vs. 10.85 ± 1.04 h, p < 0.05), complement Factor H (19.60 ± 1.84 vs. 16.80 ± 1.58 h, p < 0.05), and complement factor I (25.25 ± 1.29 vs. 19.88 ± 1.50 h, p < 0.005). Our findings suggest that an early immune response-induced inflammatory remodeling of the plasma HDL proteome precedes the diet-induced steatosis and dyslipidemia. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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18 pages, 1927 KiB

Open AccessArticle

The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification

by Estella Zuccolo, Ileana Badi, Francesco Scavello, Irene Gambuzza, Luigi Mancinelli, Federica Macrì, Calogero C. Tedesco, Fabrizio Veglia, Anna Rita Bonfigli, Fabiola Olivieri and Angela Raucci

Int. J. Mol. Sci. 2020, 21(12), 4454; https://doi.org/10.3390/ijms21124454 - 23 Jun 2020

Cited by 26 | Viewed by 4162

Abstract

The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. [...] Read more.

The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component IL6 in in vitro and in vivo models. miR-34a and IL6 levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced IL6 secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including IL6, pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant IL6 expression, with an overdose of vitamin D, was reduced in male C57BL/6J Mir34a^−/− mice. Finally, a positive correlation was observed between circulating miR-34a and IL6 in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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15 pages, 4388 KiB

Open AccessArticle

The Apolipoprotein A-I Mimetic L-4F Attenuates Monocyte Activation and Adverse Cardiac Remodeling after Myocardial Infarction

by Tariq Hamid, Mohamed Ameen Ismahil, Shyam S. Bansal, Bindiya Patel, Mehak Goel, C. Roger White, G. M. Anantharamaiah and Sumanth D. Prabhu

Int. J. Mol. Sci. 2020, 21(10), 3519; https://doi.org/10.3390/ijms21103519 - 15 May 2020

Cited by 7 | Viewed by 3228

Abstract

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we [...] Read more.

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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17 pages, 2575 KiB

Open AccessArticle

Autocrine Bradykinin Release Promotes Ischemic Preconditioning-Induced Cytoprotection in Bovine Aortic Endothelial Cells

by Alessandro Bellis, Daniela Sorriento, Antonella Fiordelisi, Raffaele Izzo, Junichi Sadoshima, Ciro Mauro, Federica Cerasuolo, Costantino Mancusi, Emanuele Barbato, Emanuele Pilato, Bruno Trimarco and Carmine Morisco

Int. J. Mol. Sci. 2020, 21(8), 2965; https://doi.org/10.3390/ijms21082965 - 23 Apr 2020

Cited by 10 | Viewed by 3133

Abstract

The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing [...] Read more.

The aims of this study were to assess whether ischemic preconditioning (PC) induces bradykinin (Bk) synthesis in bovine aortic endothelial cells (bAECs) and, if so, to explore the molecular mechanisms by which this peptide provides cytoprotection against hypoxia. PC was induced by exposing bAECs to three cycles of 15 min of hypoxia followed by 15 min of reoxygenation. Bk synthesis peaked in correspondence to the early and late phases of PC (10⁻¹² M and 10⁻¹¹ M, respectively) and was abolished by a selective tissue kallikrein inhibitor, aprotinin. Stimulation with exogenous Bk at concentrations of 10⁻¹² M and 10⁻¹¹ M reduced the cell death induced by 12 h of hypoxia by 50%. Pretreatment with HOE−140, a Bk receptor 2 (BKR2) inhibitor, in bAECs exposed to 12 h of hypoxia, abrogated the cytoprotective effect of early and late PC, whereas des-Arg-HOE-140, a Bk receptor 1 (BKR1) inhibitor, affected only the late PC. In addition, we found that PC evoked endocytosis and the recycling of BKR2 during both the early and late phases, and that inhibition of these pathways affected PC-mediated cytoprotection. Finally, we evaluated the activation of PKA and Akt in the presence or absence of BKR2 inhibitor. HOE-140 abrogated PKA and Akt activation during both early and late PC. Consistently, BKR2 inhibition abolished cross-talk between PKA and Akt in PC. In bAECs, Bk-synthesis evoked by PC mediates the protection against both apoptotic and necrotic hypoxia-induced cell death in an autocrine manner, by both BKR2- and BKR1-dependent mechanisms. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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20 pages, 1099 KiB

Open AccessArticle

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation

by Eva Schütz, Rajinikanth Gogiraju, Maria Pavlaki, Ioannis Drosos, George S. Georgiadis, Christos Argyriou, Amina Rim Ben Hallou, Fotios Konstantinou, Dimitrios Mikroulis, Rebecca Schüler, Magdalena L. Bochenek, Sogol Gachkar, Katja Buschmann, Mareike Lankeit, Susanne H. Karbach, Thomas Münzel, Dimitrios Tziakas, Stavros Konstantinides and Katrin Schäfer

Int. J. Mol. Sci. 2020, 21(1), 282; https://doi.org/10.3390/ijms21010282 - 31 Dec 2019

Cited by 16 | Viewed by 4524

Abstract

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male [...] Read more.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks (“middle-aged”) were compared to tissue or cells from mice aged 16 weeks (“adult”). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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Review

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20 pages, 1505 KiB

Open AccessReview

Hyperhomocysteinemia and Cardiovascular Disease: Is the Adenosinergic System the Missing Link?

by Franck Paganelli, Giovanna Mottola, Julien Fromonot, Marion Marlinge, Pierre Deharo, Régis Guieu and Jean Ruf

Int. J. Mol. Sci. 2021, 22(4), 1690; https://doi.org/10.3390/ijms22041690 - 8 Feb 2021

Cited by 50 | Viewed by 6417

Abstract

The influence of hyperhomocysteinemia (HHCy) on cardiovascular disease (CVD) remains unclear. HHCy is associated with inflammation and atherosclerosis, and it is an independent risk factor for CVD, stroke and myocardial infarction. However, homocysteine (HCy)-lowering therapy does not affect the inflammatory state of CVD [...] Read more.

The influence of hyperhomocysteinemia (HHCy) on cardiovascular disease (CVD) remains unclear. HHCy is associated with inflammation and atherosclerosis, and it is an independent risk factor for CVD, stroke and myocardial infarction. However, homocysteine (HCy)-lowering therapy does not affect the inflammatory state of CVD patients, and it has little influence on cardiovascular risk. The HCy degradation product hydrogen sulfide (H₂S) is a cardioprotector. Previous research proposed a positive role of H₂S in the cardiovascular system, and we discuss some recent data suggesting that HHCy worsens CVD by increasing the production of H₂S, which decreases the expression of adenosine A_2A receptors on the surface of immune and cardiovascular cells to cause inflammation and ischemia, respectively. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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13 pages, 7060 KiB

Open AccessReview

The Cardiovascular Phenotype in Fabry Disease: New Findings in the Research Field

by Daniela Sorriento and Guido Iaccarino

Int. J. Mol. Sci. 2021, 22(3), 1331; https://doi.org/10.3390/ijms22031331 - 29 Jan 2021

Cited by 14 | Viewed by 3853

Abstract

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) [...] Read more.

Fabry disease (FD) is a lysosomal storage disorder, depending on defects in alpha-galactosidase A (GAL) activity. At the clinical level, FD shows a high phenotype variability. Among them, cardiovascular dysfunction is often recurrent or, in some cases, is the sole symptom (cardiac variant) representing the leading cause of death in Fabry patients. The existing therapies, besides specific symptomatic treatments, are mainly based on the restoration of GAL activity. Indeed, mutations of the galactosidase alpha gene (GLA) cause a reduction or lack of GAL activity leading to globotriaosylceramide (Gb3) accumulation in several organs. However, several other mechanisms are involved in FD’s development and progression that could become useful targets for therapeutics. This review discusses FD’s cardiovascular phenotype and the last findings on molecular mechanisms that accelerate cardiac cell damage. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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22 pages, 1230 KiB

Open AccessReview

Adaptive Immune Responses in Human Atherosclerosis

by Silvia Lee, Benjamin Bartlett and Girish Dwivedi

Int. J. Mol. Sci. 2020, 21(23), 9322; https://doi.org/10.3390/ijms21239322 - 7 Dec 2020

Cited by 18 | Viewed by 4029

Abstract

Atherosclerosis is a chronic inflammatory disease that is initiated by the deposition and accumulation of low-density lipoproteins in the artery wall. In this review, we will discuss the role of T- and B-cells in human plaques at different stages of atherosclerosis and the [...] Read more.

Atherosclerosis is a chronic inflammatory disease that is initiated by the deposition and accumulation of low-density lipoproteins in the artery wall. In this review, we will discuss the role of T- and B-cells in human plaques at different stages of atherosclerosis and the utility of profiling circulating immune cells to monitor atherosclerosis progression. Evidence supports a proatherogenic role for intraplaque T helper type 1 (Th1) cells, CD4⁺CD28^null T-cells, and natural killer T-cells, whereas Th2 cells and regulatory T-cells (Treg) have an atheroprotective role. Several studies indicate that intraplaque T-cells are activated upon recognition of endogenous antigens including heat shock protein 60 and oxidized low-density lipoprotein, but antigens derived from pathogens can also trigger T-cell proliferation and cytokine production. Future studies are needed to assess whether circulating cellular biomarkers can improve identification of vulnerable lesions so that effective intervention can be implemented before clinical manifestations are apparent. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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19 pages, 2873 KiB

Open AccessReview

Cardiovascular Active Peptides of Marine Origin with ACE Inhibitory Activities: Potential Role as Anti-Hypertensive Drugs and in Prevention of SARS-CoV-2 Infection

by Marco Festa, Clementina Sansone, Christophe Brunet, Fabio Crocetta, Luisa Di Paola, Michele Lombardo, Antonino Bruno, Douglas M. Noonan and Adriana Albini

Int. J. Mol. Sci. 2020, 21(21), 8364; https://doi.org/10.3390/ijms21218364 - 7 Nov 2020

Cited by 19 | Viewed by 6436

Abstract

Growing interest in hypertension—one of the main factors characterizing the cardiometabolic syndrome (CMS)—and anti-hypertensive drugs raised from the emergence of a new coronavirus, SARS-CoV-2, responsible for the COVID19 pandemic. The virus SARS-CoV-2 employs the Angiotensin-converting enzyme 2 (ACE2), a component of the RAAS [...] Read more.

Growing interest in hypertension—one of the main factors characterizing the cardiometabolic syndrome (CMS)—and anti-hypertensive drugs raised from the emergence of a new coronavirus, SARS-CoV-2, responsible for the COVID19 pandemic. The virus SARS-CoV-2 employs the Angiotensin-converting enzyme 2 (ACE2), a component of the RAAS (Renin-Angiotensin-Aldosterone System) system, as a receptor for entry into the cells. Several classes of synthetic drugs are available for hypertension, rarely associated with severe or mild adverse effects. New natural compounds, such as peptides, might be useful to treat some hypertensive patients. The main feature of ACE inhibitory peptides is the location of the hydrophobic residue, usually Proline, at the C-terminus. Some already known bioactive peptides derived from marine resources have potential ACE inhibitory activity and can be considered therapeutic agents to treat hypertension. Peptides isolated from marine vertebrates, invertebrates, seaweeds, or sea microorganisms displayed important biological activities to treat hypertensive patients. Here, we reviewed the anti-hypertensive activities of bioactive molecules isolated/extracted from marine organisms and discussed the associated molecular mechanisms involved. We also examined ACE2 modulation in sight of SARS2-Cov infection prevention. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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18 pages, 2244 KiB

Open AccessReview

Neutrophils as a Novel Target of Modified Low-Density Lipoproteins and an Accelerator of Cardiovascular Diseases

by Takashi Obama and Hiroyuki Itabe

Int. J. Mol. Sci. 2020, 21(21), 8312; https://doi.org/10.3390/ijms21218312 - 5 Nov 2020

Cited by 22 | Viewed by 5066

Abstract

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein [...] Read more.

Neutrophil extracellular traps (NETs) significantly contribute to various pathophysiological conditions, including cardiovascular diseases. NET formation in the vasculature exhibits inflammatory and thrombogenic activities on the endothelium. NETs are induced by various stimulants such as exogenous damage-associated molecular patterns (DAMPs). Oxidatively modified low-density lipoprotein (oxLDL) has been physiologically defined as a subpopulation of LDL that comprises various oxidative modifications in the protein components and oxidized lipids, which could act as DAMPs. oxLDL has been recognized as a crucial initiator and accelerator of atherosclerosis through foam cell formation by macrophages; however, recent studies have demonstrated that oxLDL stimulates neutrophils to induce NET formation and enhance NET-mediated inflammatory responses in vascular endothelial cells, thereby suggesting that oxLDL may be involved in cardiovascular diseases through neutrophil activation. As NETs comprise myeloperoxidase and proteases, they have the potential to mediate oxidative modification of LDL. This review summarizes recent updates on the analysis of NETs, their implications for cardiovascular diseases, and prospects for a possible link between NET formation and oxidative modification of lipoproteins. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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27 pages, 2100 KiB

Open AccessReview

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis

by Denisa Baci, Annalisa Bosi, Luca Parisi, Giuseppe Buono, Lorenzo Mortara, Giuseppe Ambrosio and Antonino Bruno

Int. J. Mol. Sci. 2020, 21(19), 7165; https://doi.org/10.3390/ijms21197165 - 28 Sep 2020

Cited by 40 | Viewed by 5668

Abstract

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression [...] Read more.

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in “sterile” inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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18 pages, 616 KiB

Open AccessReview

VEGF-A in Cardiomyocytes and Heart Diseases

by Mariantonia Braile, Simone Marcella, Leonardo Cristinziano, Maria Rosaria Galdiero, Luca Modestino, Anne Lise Ferrara, Gilda Varricchi, Giancarlo Marone and Stefania Loffredo

Int. J. Mol. Sci. 2020, 21(15), 5294; https://doi.org/10.3390/ijms21155294 - 26 Jul 2020

Cited by 156 | Viewed by 15784

Abstract

The vascular endothelial growth factor (VEGF), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis. Angiogenesis, the formation of new blood vessels, is responsible for a wide variety of physio/pathological processes, including cardiovascular diseases (CVD). Cardiomyocytes (CM), the main cell type present [...] Read more.

The vascular endothelial growth factor (VEGF), a homodimeric vasoactive glycoprotein, is the key mediator of angiogenesis. Angiogenesis, the formation of new blood vessels, is responsible for a wide variety of physio/pathological processes, including cardiovascular diseases (CVD). Cardiomyocytes (CM), the main cell type present in the heart, are the source and target of VEGF-A and express its receptors, VEGFR1 and VEGFR2, on their cell surface. The relationship between VEGF-A and the heart is double-sided. On the one hand, VEGF-A activates CM, inducing morphogenesis, contractility and wound healing. On the other hand, VEGF-A is produced by CM during inflammation, mechanical stress and cytokine stimulation. Moreover, high concentrations of VEGF-A have been found in patients affected by different CVD, and are often correlated with an unfavorable prognosis and disease severity. In this review, we summarized the current knowledge about the expression and effects of VEGF-A on CM and the role of VEGF-A in CVD, which are the most important cause of disability and premature death worldwide. Based on clinical studies on angiogenesis therapy conducted to date, it is possible to think that the control of angiogenesis and VEGF-A can lead to better quality and span of life of patients with heart disease. Full article

(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions 2.0)

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