scholarly journals Angiotensin II-Induced Cardiovascular Fibrosis Is Attenuated by NO-Sensitive Guanylyl Cyclase1

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2436
Author(s):  
Kathrin Broekmans ◽  
Jan Giesen ◽  
Lukas Menges ◽  
Doris Koesling ◽  
Michael Russwurm
Keyword(s):  
Cardiovascular System ◽  
Cardiac Remodeling ◽  
Interstitial Fibrosis ◽  
Therapeutic Implications ◽  
Cgmp Signaling ◽  
Mrna Content ◽  
Perivascular Area ◽  
Cardiovascular Fibrosis ◽  
The Impact ◽  
Deficient Mice

In the NO/cGMP signaling cascade, relevant in the cardiovascular system, two NO-sensitive guanylyl cyclase (NO-GC) isoforms are responsible for NO-dependent cGMP generation. Here, the impact of the major NO-GC isoform, NO-GC1, on fibrosis development in the cardiovascular system was studied in NO-GC1-deficient mice treated with AngiotensinII (AngII), known to induce vascular and cardiac remodeling. Morphometric analysis of NO-GC1 KO’s aortae demonstrated an enhanced increase of perivascular area after AngII treatment accompanied by a higher aortic collagen1 mRNA content. Increased perivascular fibrosis also occurred in cardiac vessels of AngII-treated NO-GC1 KO mice. In line, AngII-induced interstitial fibrosis was 32% more pronounced in NO-GC1 KO than in WT myocardia associated with a higher cardiac Col1 and other fibrotic marker protein content. In sum, increased perivascular and cardiac interstitial fibrosis together with the enhanced collagen1 mRNA content in AngII-treated NO-GC1-deficient mice represent an exciting manifestation of antifibrotic properties of cGMP formed by NO-GC1, a finding with great pharmaco-therapeutic implications.

scholarly journals Therapeutic Implications for PDE2 and cGMP/cAMP Mediated Crosstalk in Cardiovascular Diseases

2020 ◽  
Vol 21 (20) ◽  
pp. 7462
Author(s):  
Mirna S. Sadek ◽  
Eleder Cachorro ◽  
Ali El-Armouche ◽  
Susanne Kämmerer
Keyword(s):  
Cardiovascular Diseases ◽  
Cardiovascular System ◽  
Comprehensive Overview ◽  
Therapeutic Implications ◽  
Secondary Messengers ◽  
Cgmp Signaling ◽  
Cardiovascular Pathologies ◽  
Regulatory Functions ◽  
Cellular Components ◽  
Camp And Cgmp

Phosphodiesterases (PDEs) are the principal superfamily of enzymes responsible for degrading the secondary messengers 3′,5′-cyclic nucleotides cAMP and cGMP. Their refined subcellular localization and substrate specificity contribute to finely regulate cAMP/cGMP gradients in various cellular microdomains. Redistribution of multiple signal compartmentalization components is often perceived under pathological conditions. Thereby PDEs have long been pursued as therapeutic targets in diverse disease conditions including neurological, metabolic, cancer and autoimmune disorders in addition to numerous cardiovascular diseases (CVDs). PDE2 is a unique member of the broad family of PDEs. In addition to its capability to hydrolyze both cAMP and cGMP, PDE2 is the sole isoform that may be allosterically activated by cGMP increasing its cAMP hydrolyzing activity. Within the cardiovascular system, PDE2 serves as an integral regulator for the crosstalk between cAMP/cGMP pathways and thereby may couple chronically adverse augmented cAMP signaling with cardioprotective cGMP signaling. This review provides a comprehensive overview of PDE2 regulatory functions in multiple cellular components within the cardiovascular system and also within various subcellular microdomains. Implications for PDE2- mediated crosstalk mechanisms in diverse cardiovascular pathologies are discussed highlighting the prospective use of PDE2 as a potential therapeutic target in cardiovascular disorders.

Abstract P173: The Impact Of Cigarette Smoking-oral Contraceptive Combination On Cardiac Remodeling In Premenopausal Female Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Emna Abidi ◽  
ABDULLAH KAPLAN ◽  
Rana Ghali ◽  
George W Booz ◽  
Abdo Jurjus ◽  
...  
Keyword(s):  
Oral Contraceptive ◽  
Ejection Fraction ◽  
Cardiac Remodeling ◽  
Ethinyl Estradiol ◽  
Interstitial Fibrosis ◽  
Western Blots ◽  
Functional Changes ◽  
Female Mice ◽  
Premenopausal Female ◽  
The Impact

Introduction: Tobacco smoke is a major risk factor for coronary artery diseases (CAD) and chronic tobacco smoking (CS) increase the risk of CAD by 2 to 4 folds. CS effect on cardiac homeostasis has never been evaluated in premenopausal females taking oral contraceptive (OC). This study investigates CS effect on cardiac remodeling in female mice in the presence or absence of Ethinyl Estradiol (EE). Methods: Blood pressure and echocardiography were recorded for female C57BL/6J mice on EE, EE-CS, vehicle, and vehicle-CS at baseline and after 8-weeks of exposure. Cardiac inflammatory cytokines and oxidative stress markers were evaluated by real time PCR and western blots. Interstitial collagen deposition was assessed by Masson Trichrome staining. Results: Eight weeks of EE-CS treated mice showed no effect on BP but significant adverse structural and functional cardiac effects, represented by increased systolic (0.981 ± 0.035 N=11 (p<0.0332)) and diastolic (1.450 ± 0.037 N=11 (p<0.0002)) areas when compared to the vehicle and EE groups, along with increased systolic (1.981 ± 0.109 N=11 (p<0.033)) and diastolic ( 3.911 ± 0.159 N=11 (p<0.033)) volumes when compared to all groups. Functional changes were accompanied with a decreased fractional shortening (9.194 ± 1.006 N=11 (p<0.033)) when compared to vehicle and EE groups with no changes in ejection fraction parameter. Moreover EE-CS treatment significantly increased NOX-4 expression (2.297 ± 0.643 N=5 (p<0.033)) when compared to EE treatment alone, along with an increased pro-inflammatory profile including IL-1β (0.750 ±0.171N=5 (p<0.033)) and IL-4 (4.110 ± 0.623 N= 5 (p<0.002)) when compared to all groups, and IL-6 (3.045±0.910 N=5 (p<0.002)) and IL-13 (2.686 ± 0.648 N=5 (p<0.033)) when compared to vehicle-CS group. Morphologically, EE-CS exhibited a significant increase in interstitial fibrosis (1.186± 0.020 N=5, 3.2285 ± 0.683 N=5, (p<0.033)) when compared to the vehicle-CS group. Conclusion: This study provides clear evidence that CS-exposed premenopausal female mice on OC regimen exhibited significant adverse cardiac events that could be classified under cardiac dysfunction with preserved ejection fraction. Additional experiments are warranted to further elaborate on these findings.

IDENTIFICATION AND ASSESSMENT OF RISK FACTORS ROLE IN MYOCARDIAL INFARCTION DEVELOPMENT

2019 ◽  
Vol 72 (5) ◽  
pp. 779-783
Author(s):  
Victor A. Ognev ◽  
Anna A. Podpriadova ◽  
Anna V. Lisova
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Cardiovascular Disease ◽  
Cardiovascular System ◽  
Control Group ◽  
Biological Factors ◽  
Prevention And Treatment ◽  
High Level ◽  
Social Importance ◽  
The Impact

Introduction:The high level of morbidity and mortality from cardiovascular disease is largely due toinsufficient influence on the main risk factors that contribute to the development of myocardial infarction.Therefore, a detailed study and assessment of risk factors is among the most important problems of medical and social importance. The aim: To study and evaluate the impact of biological, social and hygienic, social and economic, psychological, natural and climatic risk factors on the development of myocardial infarction. Materials and methods: A sociological survey was conducted in 500 people aged 34 to 85. They were divided into two groups. The main group consisted of 310 patients with myocardial infarction. The control group consisted of 190 practically healthy people, identical by age, gender and other parameters, without diseases of the cardiovascular system. Results: It was defined that 30 factors have a significant impact on the development of myocardial infarction.Data analysis revealed that the leading risk factors for myocardial infarction were biological and socio-hygienic. The main biological factors were: hypertension and hypercholesterolemia. The man socio-hygienic factor was smoking. Conclusions: Identification of risk factors provides new opportunities for the development of more effective approaches for the prevention and treatment of myocardial infarction.

The Impact of Translational Research in Breast Cancer Care: Can we Improve the Therapeutic Scenario?

2018 ◽  
Vol 18 (6) ◽  
pp. 832-836
Author(s):  
Giuseppe Buono ◽  
Francesco Schettini ◽  
Francesco Perri ◽  
Grazia Arpino ◽  
Roberto Bianco ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Translational Research ◽  
Cell Biology ◽  
Cancer Biology ◽  
Hormone Receptors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Molecular Heterogeneity ◽  
Therapeutic Implications ◽  
The Impact

Traditionally, breast cancer (BC) is divided into different subtypes defined by immunohistochemistry (IHC) according to the expression of hormone receptors and overexpression/amplification of human epidermal growth factor receptor 2 (HER2), with crucial therapeutic implications. In the last few years, the definition of different BC molecular subgroups within the IHC-defined subtypes and the identification of the important role that molecular heterogeneity can play in tumor progression and treatment resistance have inspired the search for personalized therapeutic approaches. In this scenario, translational research represents a key strategy to apply knowledge from cancer biology to the clinical setting, through the study of all the tumors “omics”, including genomics, transcriptomics, proteomics, epigenomics, and metabolomics. Importantly, the introduction of new high-throughput technologies, such as next generation sequencing (NGS) for the study of cancer genome and transcriptome, greatly amplifies the potential and the applications of translational research in the oncology field. Moreover, the introduction of new experimental approaches, such as liquid biopsy, as well as new-concept clinical trials, such as biomarker-driven adaptive studies, may represent a turning point for BC translational research. </P><P> It is likely that translational research will have in the near future a significant impact on BC care, especially by giving us the possibility to dissect the complexity of tumor cell biology and develop new personalized treatment strategies.

scholarly journals Impact of immunogenicity on clinical efficacy and toxicity profile of biologic agents used for treatment of inflammatory arthritis in children compared to adults

2021 ◽  
Vol 13 ◽  
pp. 1759720X2110026
Author(s):  
Chinar R. Parikh ◽  
Jaya K. Ponnampalam ◽  
George Seligmann ◽  
Leda Coelewij ◽  
Ines Pineda-Torra ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Efficacy ◽  
Inflammatory Arthritis ◽  
Biologic Agents ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Biologic Drugs ◽  
Therapeutic Implications ◽  
The Impact ◽  
First Time

The treatment of inflammatory arthritis has been revolutionised by the introduction of biologic treatments. Many biologic agents are currently licensed for use in both paediatric and adult patients with inflammatory arthritis and contribute to improved disease outcomes compared with the pre-biologic era. However, immunogenicity to biologic agents, characterised by an immune reaction leading to the production of anti-drug antibodies (ADAs), can negatively impact the therapeutic efficacy of biologic drugs and induce side effects to treatment. This review explores for the first time the impact of immunogenicity against all licensed biologic treatments currently used in inflammatory arthritis across age, and will examine any significant differences between ADA prevalence, titres and timing of development, as well as ADA impact on therapeutic drug levels, clinical efficacy and side effects between paediatric and adult patients. In addition, we will investigate factors associated with differences in immunogenicity across biologic agents used in inflammatory arthritis, and their potential therapeutic implications.

scholarly journals LINC-25. BRAF ABERRATIONS IN PEDIATRIC PILOCYTIC ASTROCYTOMAS (PCAs): PREVALENCE AND IMPACT ON CLINICAL OUTCOME

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii383-iii383
Author(s):  
Subramaniam Ramanathan ◽  
Maya Prasad ◽  
Tushar Vora ◽  
Mamta Gurav ◽  
Ayushi Sahay ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Statistical Significance ◽  
Tumor Resection ◽  
Brafv600e Mutation ◽  
Therapeutic Implications ◽  
Pilocytic Astrocytomas ◽  
Ffpe Tissues ◽  
Braf Fusion ◽  
Poor Outcomes ◽  
The Impact

Abstract BACKGROUND Increasing knowledge on pilocytic astrocytoma (PCA) biology now points towards an aberration in BRAF/MAPK/ERK pathway which has both diagnostic and therapeutic implications. This study was done to note the impact of BRAF aberrations on clinical outcome in childhood PCA. METHODS FFPE tissues of all childhood PCA diagnosed during 2011–2017 were evaluated for BRAFV600E mutation by Sanger sequencing and KIAA1549 fusion transcripts (16–9;15–9;16-11) by reverse transcriptase polymerase chain reaction. Children undergoing gross tumor resection received no adjuvant treatment. Unresectable tumors (only biopsy) and NF-1 associated PCAs, were treated if clinically indicated. Only patients with documented therapy details/followup were included for analysis. STUDY RESULTS Ninety-eight patients (median age-7.7yrs; boy:girl ratio-1.4) were included. Major sites were: Cerebellum-37(38%), 3rd Ventricle-26(27%), Cerebrum-15(15%). While BRAFV600E mutation was noted in 7/89(8%) specimens, BRAF-fusions were found in 34/85(40%). Following surgery/biopsy, 23(24%) and 21(22%) received adjuvant chemotherapy and radiotherapy respectively. The 1-year/3-year/5-year-EFS of the overall cohort was 90.7%/81.3%/67.4% respectively. Cerebellar tumors did better vis-à-vis other sites(5yr-EFS:74.3% v/s 66.4%;p=0.403). The 5yr-EFS of BRAF-fusion positive tumors (34), tumors without any BRAF aberration (40) and BRAFV600E mutant tumors (7) was 84.8%/ 69.6%/ 42.9% (p=0.215). CONCLUSIONS BRAF-fusion and BRAFV600E mutation were associated with good and poor outcomes respectively. Lack of statistical significance could be attributed to use of radiation as planned therapy in patients from earlier years. Data on BRAF aberrations in PCAs aids decision making regarding adjuvant therapy and choosing appropriate salvage-therapy especially in relapsed/refractory PCAs.

Obstructive nephropathy and renal fibrosis

2002 ◽  
Vol 283 (5) ◽  
pp. F861-F875 ◽  
Author(s):  
Saulo Klahr ◽  
Jeremiah Morrissey
Keyword(s):  
Renal Disease ◽  
Renal Fibrosis ◽  
Interstitial Fibrosis ◽  
Rodent Model ◽  
Renal Diseases ◽  
Obstructive Nephropathy ◽  
Therapeutic Approaches ◽  
Cellular Events ◽  
The Impact ◽  
Made In

Interstitial fibrosis has a major role in the progression of renal diseases. Several animal models are available for the study of renal fibrosis. The models of aminonucleoside-induced nephrotic syndrome, cyclosporin nephrotoxicity, and passive Heyman nephritis are characterized by molecular and cellular events similar to those that occur in obstructive nephropathy. Additionally, inhibition of angiotensin-converting enzyme exerts salutary effects on the progression of renal fibrosis in obstructive nephropathy. Unilateral ureteral obstruction (UUO) has emerged as an important model for the study of the mechanisms of renal fibrosis and also for the evaluation of the impact of potential therapeutic approaches to ameliorate renal disease. Many quantifiable pathophysiological events occur over the span of 1 wk of UUO, making this an attractive model for study. This paper reviews some of the ongoing studies that utilized a rodent model of UUO. Some of the findings of the animal model have been compared with observations made in patients with obstructive nephropathy. Most of the evidence suggests that the rodent model of UUO is reflective of human renal disease processes.

The state of the cardiovascular system in occupational bronchitis and chronic obstructive pulmonary disease, not associated with the impact of harmful industrial factors

2021 ◽  
pp. 55-68
Author(s):  
Vyacheslav S. Lotkov ◽  
Anton Vladimirovich Glazistov ◽  
Antonina G. Baykova ◽  
Marina Yuryevna Vostroknutova ◽  
Natalia E. Lavrentieva
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Cardiovascular System ◽  
Pulmonary Disease ◽  
Lung Diseases ◽  
Chronic Obstructive ◽  
External Respiration ◽  
Obstructive Pulmonary Disease ◽  
Occupational Lung Diseases ◽  
The Right ◽  
The Impact

The formation and progression of chronic dust bronchitis and chronic bronchitis of toxic-chemical etiology, chronic obstructive pulmonary disease is accompanied by an increase in the degree of ventilation disorders, echocardiographic signs of hypertrophy and dilatation of the right ventricle are formed, typical for chronic pulmonary heart disease. The progression of disturbances in the function of external respiration in dusty lung diseases leads to a decrease in myocardial contractility. The detection of hemodynamic disturbances at the early stages of the development of occupational lung diseases indicates the need for individual monitoring of the functional state of the cardiovascular system in the process of contact with industrial aerosols, especially in groups of workers with long-term exposure.

scholarly journals Impaired hypoxic pulmonary vasoconstriction in a mouse model of Leigh syndrome

2019 ◽  
Vol 316 (2) ◽  
pp. L391-L399 ◽  
Author(s):  
Grigorij Schleifer ◽  
Eizo Marutani ◽  
Michele Ferrari ◽  
Rohit Sharma ◽  
Owen Skinner ◽  
...  
Keyword(s):  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Inflammation ◽  
Leigh Syndrome ◽  
Arterial Oxygen ◽  
Inborn Errors ◽  
Pulmonary Vasoconstriction ◽  
Progressive Encephalopathy ◽  
Alveolar Hypoxia ◽  
The Impact ◽  
Deficient Mice

Hypoxic pulmonary vasoconstriction (HPV) is a physiological vasomotor response that maintains systemic oxygenation by matching perfusion to ventilation during alveolar hypoxia. Although mitochondria appear to play an essential role in HPV, the impact of mitochondrial dysfunction on HPV remains incompletely defined. Mice lacking the mitochondrial complex I (CI) subunit Ndufs4 ( Ndufs4−/−) develop a fatal progressive encephalopathy and serve as a model for Leigh syndrome, the most common mitochondrial disease in children. Breathing normobaric 11% O2 prevents neurological disease and improves survival in Ndufs4−/− mice. In this study, we found that either genetic Ndufs4 deficiency or pharmacological inhibition of CI using piericidin A impaired the ability of left mainstem bronchus occlusion (LMBO) to induce HPV. In mice breathing air, the partial pressure of arterial oxygen during LMBO was lower in Ndufs4−/− and in piericidin A-treated Ndufs4+/+ mice than in respective controls. Impairment of HPV in Ndufs4−/− mice was not a result of nonspecific dysfunction of the pulmonary vascular contractile apparatus or pulmonary inflammation. In Ndufs4-deficient mice, 3 wk of breathing 11% O2 restored HPV in response to LMBO. When compared with Ndufs4−/− mice breathing air, chronic hypoxia improved systemic oxygenation during LMBO. The results of this study show that, when breathing air, mice with a congenital Ndufs4 deficiency or chemically inhibited CI function have impaired HPV. Our study raises the possibility that patients with inborn errors of mitochondrial function may also have defects in HPV.

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