- A polymorphism in intron I of the human angiotensinogen gene (hAGT) affects binding by HNF3 and hAGT expression and increases blood pressure in mice. [Journal Article]
- JBJ Biol Chem 2019 Jun 14
- Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin-II. Genome-wide association studies (GWAS) have shown that two A/G polymorphisms (rs2493134 and …
Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin-II. Genome-wide association studies (GWAS) have shown that two A/G polymorphisms (rs2493134 and rs2004776) located at +507 and +1164 in intron I of human AGT (hAGT) gene are associated with hypertension. Polymorphisms of the AGT gene result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and does not affect blood pressure. The nucleotide sequence of intron I of the hAGT gene containing the +1164A variant has a stronger homology with hepatocyte nuclear factor 3 (HNF3)-binding site than does +1164G. Here, we found that (a) an oligonucleotide containing +1164A binds HNF3β more strongly than does +1164G, and (b) Hap I-containing reporter gene constructs have increased basal and HNF3- and glucocorticoid-induced promoter activity in transiently transfected liver and kidney cells. Using a knock-in approach at the HPRT locus, we generated transgenic mouse model containing the human renin (hREN) gene and either Hap-I or Hap-II. We show that transgenic animals containing Hap-I have increased blood pressure compared with those containing Hap-II. Moreover, the transcription factors glucocorticoid receptor (GR), CCAAT enhancer-binding protein β (C/EBPβ), and HNF3β bound more strongly to chromatin obtained from the liver of transgenic animals containing Hap-I than to liver chromatin from Hap-II-containing animals. These findings suggest that unlike Hap-II variants, Hap-I variants of the hAGT gene have increased transcription rates, resulting in elevated blood pressure.
- Loss of GTPase activating protein neurofibromin stimulates paracrine cell communication via macropinocytosis. [Journal Article]
- RBRedox Biol 2019 May 30; :101224
- Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) tumor suppressor gene, is a negative regulator of Ras signaling. Patients with mutations in NF1 have a strong predisposition f…
Neurofibromin, the protein product of the neurofibromatosis type 1 (NF1) tumor suppressor gene, is a negative regulator of Ras signaling. Patients with mutations in NF1 have a strong predisposition for cardiovascular disease, which contributes to their early mortality. Nf1 heterozygous (Nf1+/-) bone marrow to wild type chimeras and mice with heterozygous recombination of Nf1 in myeloid cells recapitulate many of the vascular phenotypes observed in Nf1+/- mutants. Although these results suggest that macrophages play a central role in NF1 vasculopathy, the underlying mechanisms are currently unknown. In the present study, we employed macrophages isolated from either Nf1+/- or Lysm Cre+/Nf1f/f mice to test the hypothesis that loss of Nf1 stimulates macropinocytosis in macrophages. Scanning electron microscopy and flow cytometry analysis of FITC-dextran internalization demonstrated that loss of Nf1 in macrophages stimulates macropinocytosis. We next utilized various cellular and molecular approaches, pharmacological inhibitors and genetically modified mice to identify the signaling mechanisms mediating macropinocytosis in Nf1-deficient macrophages. Our results indicate that loss of Nf1 stimulates PKCδ-mediated p47phox phosphorylation via RAS activation, leading to increased NADPH oxidase 2 activity, reactive oxygen species generation, membrane ruffling and macropinocytosis. Interestingly, we also found that Nf1-deficient macrophages internalize exosomes derived from angiotensin II-treated endothelial cells via macropinocytosis in vitro and in the peritoneal cavity in vivo. As a result of exosome internalization, Nf1-deficient macrophages polarized toward an inflammatory M1 phenotype and secreted increased levels of proinflammatory cytokines compared to controls. In conclusion, the findings of the present study demonstrate that loss of Nf1 stimulates paracrine endothelial to myeloid cell communication via macropinocytosis, leading to proinflammatory changes in recipient macrophages.
- Renin-angiotensin system activation and imbalance of matrix metalloproteinase-9/tissue inhibitor of matrix metalloproteinase-1 in cold-induced stroke. [Journal Article]
- LSLife Sci 2019 Jun 11; :116563
- CONCLUSIONS: The present study is the first to demonstrate that cold exposure exacerbates imbalance between MMP-9 and TIMP-1 by activating the RAS, which may be critical in the initiation of stroke during chronic hypertension. In addition, our results suggest that captopril and rhTIMP-1 exert protective effects against cold-induced stroke by ameliorating MMP-9/TIMP-1 imbalance.
- Protective Role of Angiotensin Type 1 Receptor Blockade in 4/6 Nephrectomized Male and Female Rats. [Journal Article]
- IJInt J Prev Med 2019; 10:64
- CONCLUSIONS: Losartan may improve renal function in 4/6 nephrectomized male rats.
- Obesity and aging affects skeletal muscle renin-angiotensin system and myosin heavy chain proportions in pre-diabetic Zucker rats. [Journal Article]
- JPJ Physiol Biochem 2019 Jun 13
- There is a gap in the knowledge regarding regulation of local renin-angiotensin system (RAS) in skeletal muscle during development of obesity and insulin resistance in vivo. This study evaluates the …
There is a gap in the knowledge regarding regulation of local renin-angiotensin system (RAS) in skeletal muscle during development of obesity and insulin resistance in vivo. This study evaluates the obesity- and age-related changes in the expression of local RAS components. Since RAS affects skeletal muscle remodelling, we also evaluated the muscle fibre type composition, defined by myosin heavy chain (MyHC) mRNAs and protein content. Gene expressions were determined by qPCR and/or Western blot analysis in musculus quadriceps of 3- and 8-month-old male obese Zucker rats and their lean controls. The enzymatic activity of aminopeptidase A (APA) was determined flourometrically. Activation of renin receptor (ReR)/promyelocytic leukaemia zinc finger (PLZF) negative feedback mechanism was observed in obesity. The expression of angiotensinogen and AT1 was downregulated by obesity, while neutral endopeptidase and AT2 expressions were upregulated in obese rats with aging. Skeletal muscle APA activity was decreased by obesity, which negatively correlated with the increased plasma APA activity and plasma cholesterol. The expression of angiotensin-converting enzyme (ACE) positively correlated with MyHC mRNAs characteristic for fast-twitch muscle fibres. The obesity- and age-related alterations in the expression of both classical and alternative RAS components suggest an onset of a new equilibrium between ACE/AngII/AT1 and ACE2/Ang1-7/Mas at lower level accompanied by increased renin/ReR/PLZF activation. Increased APA release from the skeletal muscle in obesity might contribute to increased plasma APA activity. There is a link between reduced ACE expression and altered muscle MyHC proportion in obesity and aging.
- The protective effects of polysaccharide extract from Xin-Ji-Er-Kang formula on Ang II-induced HUVECs injury, L-NAME-induced hypertension and cardiovascular remodeling in mice. [Journal Article]
- BCBMC Complement Altern Med 2019 Jun 13; 19(1):127
- CONCLUSIONS: Polysaccharide from XJEK exerts protective effects against Ang II-induced injury in HUVECs and L-NAME-induced hypertension in mice and the underlying mechanism may be attributed to improving endothelial dysfunction, OS and the inflammation status in mice.
- Cutaneous effects of antihypertensive drugs. [Journal Article]
- GIG Ital Dermatol Venereol 2019 Jun 12
- CONCLUSIONS: During antihypertensive treatment, several dermatological reactions may occur. Clinicians should inform their patients of the increased risk of cutaneous lesions associated with the use of these drugs, and perform periodic examination of the skin.
- Genetic polymorphism of angiotensin converting enzyme and angiotensin II type 1 receptors and their impact on the outcome of acute coronary syndrome. [Journal Article]
- GGenomics 2019 Jun 10
- This study aims to investigate the impact of ACE (rs4343) and AT1R (rs 5182) genetic polymorphisms on the outcome of acute coronary syndrome (ACS) in patients on captopril. Two hundred and fifty part…
This study aims to investigate the impact of ACE (rs4343) and AT1R (rs 5182) genetic polymorphisms on the outcome of acute coronary syndrome (ACS) in patients on captopril. Two hundred and fifty participants with ACS were included in this study (Group 1 (120) participants on captopril 25 mg twice daily and Group 2 (130) participants received no captopril (control study)). Participants were genotyped for ACE (rs4343) and AT1R (rs5182) polymorphisms and the phenotype was determined. ACE polymorphism (rs 4343) GG and GA genotypes are more related to STEMI (OR = 1.7, 1.5 respectively) and NSTEMI (OR = 3, 3.8 respectively), and they were more prone to have Percutaneous Coronary Intervention after ACS attack (OR = 11.6, 14.1 respectively). AT1R (rs 5182) CT genotype is mildly associated with STEMI (OR = 1.1), but also prone to have PCI after ACS attack (OR = 1.6) while TT genotype has a risk to get less improvement (OR = 1.8).
- Irbesartan Ameliorates Lipid Deposition by Enhancing Autophagy via PKC/AMPK/ULK1 Axis in Free Fatty Acid Induced Hepatocytes. [Journal Article]
- FPFront Physiol 2019; 10:681
- Irbesartan has shown significant therapeutic effects in hypertensive patients with non-alcoholic fatty liver disease (NAFLD). To determine the underlying mechanisms of its action, we established an i…
Irbesartan has shown significant therapeutic effects in hypertensive patients with non-alcoholic fatty liver disease (NAFLD). To determine the underlying mechanisms of its action, we established an in vitro model of NAFLD by treating human and mouse hepatocytes with free fatty acids (FFAs) and angiotensin (Ang) II. Irbesartan significantly reversed AngII/FFA-induced lipid deposition and mitochondrial dysfunction by restoring ATP production and the mitochondrial membrane potential (MMP), and decreasing the levels of reactive oxygen species (ROS) and inflammatory markers. In addition, irbesartan also increased the autophagy flux, in terms of increased numbers of autolysosomes and autophagosomes, and the upregulation and mitochondrial localization of the autophagic proteins Atg5 and LC3BII/I. Activation of protein kinase C (PKC) and inhibition of the autophagic flux exacerbated mitochondrial dysfunction in the steatotic hepatocytes. Furthermore, AngII upregulated PKC which inhibited AMPK phosphorylation via direct interaction with the AngII receptor AT1-R. Irbesartan inhibited PKC and activated AMPK and its downstream effector ULK1, thereby inducing autophagy, decreasing lipid deposition, and restoring mitochondrial function. Taken together, irbesartan triggers autophagy via the PKC/AMPK/ULK1 axis to ameliorate the pathological changes in the steatotic hepatocytes.
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- Time Series Gene Expression Profiling and Temporal Regulatory Pathway Analysis of Angiotensin II Induced Atrial Fibrillation in Mice. [Journal Article]
- FPFront Physiol 2019; 10:597
- CONCLUSIONS: The present findings revealed that many genes are involved in Ang II-induced AF, and highlighted that Pik3cg may play a central role in this disease.