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Current Hypertension Reports May 2024The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to... (Review)
Review
PURPOSE OF REVIEW
The primary goal of this review article was to determine whether the three RAAS-associated SNPs, Renin-rs16853055, AGT-rs3789678 and ACE-rs4305 are genetically linked to the development of hypertension in preeclampsia. The secondary goal was to establish if there was a link between these SNPs and HIV infection.
RECENT FINDINGS
There is a paucity of findings related to the aforementioned SNPs and preeclampsia. There are no recent findings on the rs16853055 renin polymorphism. The rs3789678 angiotensinogen polymorphism correlated significantly with gestational hypertension. The rs4305 ACE polymorphism showed no significant association with the development of pregnancy-induced hypertension. There are conflicting findings when determining the relationship between ethnicity and the predisposition of preeclampsia and hypertension in relation to the discussed RAAS-associated SNPs. To date, the association between RAAS-associated SNPs and preeclamptic women co-morbid with HIV in South Africa has revealed that certain alleles of the AGT gene are more prominent in HIV-infected PE compared to normotensive pregnant HIV-infected women.
Topics: Humans; Pregnancy; Female; Pre-Eclampsia; HIV Infections; Polymorphism, Single Nucleotide; Angiotensinogen; Renin-Angiotensin System; Renin; Peptidyl-Dipeptidase A; Genetic Predisposition to Disease; Pregnancy Complications, Infectious
PubMed: 38411777
DOI: 10.1007/s11906-023-01292-y -
Saudi Pharmaceutical Journal : SPJ :... Sep 2023Metabolic Syndrome (MetS) is a term used to describe a cluster of pathophysiological, biochemical, and metabolic criteria; including high Blood Pressure (BP), high...
Metabolic Syndrome (MetS) is a term used to describe a cluster of pathophysiological, biochemical, and metabolic criteria; including high Blood Pressure (BP), high cholesterol, dyslipidaemia, central obesity and Insulin Resistance (IR). The Renin Angiotensin System (RAS) has a regulatory function in BP, hydroelectrolyte balance, and cardiovascular function. RAS is composed of angiotensinogen (AGT), (Ang I), (Ang II), (ACE1), (ACE2), (AT1R), (AT2R), and (Ang 1-7). Vitamin D had been proved to act as a protective factor against MetS. Therefore, the study is pursued to explore vitamin D supplementation roles on hepatic RAS in MetS experimental model. At first, 36 males Albino rats were separated into 4 groups and induced to MetS under controlled circumstances for 3 months. Then, data were collected from blood samples, whereas RNA extracted from liver were analyzed using biochemical and statistical analysis tests. As a result, the major finding was proving that vitamin D can balance the expression of and . Also, confirming that it can improve MetS components by elevating HDL and insulin levels while reducing the levels of BP, cholesterol, LDL, TG, GLU, ALT, AST, and IR. These outcomes may give a new insight into the RAS pathways associated with MetS.
PubMed: 37559868
DOI: 10.1016/j.jsps.2023.101709 -
BioRxiv : the Preprint Server For... Nov 2023Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development.
BACKGROUND
Acinar ductal metaplasia (ADM) is among the earliest initiating events in pancreatic ductal adenocarcinoma (PDAC) development.
METHODS
We developed a novel morphology-based screen using organoids from wildtype and p48 (Cre) mice to discover epigenetic modulators that inhibit or reverse pancreatic ADM more effectively than the broad-spectrum HDAC inhibitor trichostatin A (TSA).
RESULTS
Of the 144 compounds screened, nine hits and two additional natural product HDAC inhibitors were validated by dose-response analysis. The class I HDAC inhibitors apicidin and FK228, and the histone methyltransferase inhibitor chaetocin demonstrated pronounced ADM inhibition and reversal without inducing significant cytotoxicity at 1 µM. Thioester prodrug class I HDAC inhibitor largazole attenuated ADM while its disulfide homodimer was effective in both ADM inhibition and reversal. Prioritized compounds were validated for ADM reversal in p48 ;LSL-Kras (KC) mouse organoids using both morphological and molecular endpoints. Molecular index analysis of ADM reversal in KC mouse organoids demonstrated improved activity compared to TSA. Improved prodrug stability translated into a stronger phenotypic and molecular response. RNA-sequencing indicated that angiotensinogen was the top inhibited pathway during ADM reversal.
CONCLUSION
Our findings demonstrate a unique epigenetic mechanism and suggest that the phenotypic screen developed here may be applied to discover potential treatments for PDAC.
PubMed: 38077007
DOI: 10.1101/2023.11.27.567685 -
Hypertension (Dallas, Tex. : 1979) May 2024Angiotensin-(1-12), measured by a self-developed, polyclonal antibody-based radioimmunoassay, has been suggested to act as an alternative precursor of angiotensin II. A...
BACKGROUND
Angiotensin-(1-12), measured by a self-developed, polyclonal antibody-based radioimmunoassay, has been suggested to act as an alternative precursor of angiotensin II. A more reliable detection method would be liquid chromatography-tandem mass spectrometry.
METHODS
We set up the quantification of human and murine angiotensin-(1-12) by liquid chromatography-tandem mass spectrometry and then used this method to measure angiotensin-(1-12) in human and mouse blood samples, as well as in mouse brain and kidney. We also verified ex vivo angiotensin-(1-12) generation and metabolism in human blood samples incubated at 37 °C.
RESULTS
Stabilization of blood in guanidine hydrochloride was chosen for sample collection since this allowed full recovery of spiked angiotensin-(1-12). Angiotensin-(1-12) was undetectable in human blood samples when incubating nonstabilized plasma at 37 °C, while angiotensin-(1-12) added to nonstabilized human plasma disappeared within 10 minutes. Stabilized human blood samples contained angiotensin II, while angiotensin-(1-12) was undetectable. Blood, hearts, and kidneys, but not brains, of wild-type mice and rats contained detectable levels of angiotensin II, while angiotensin-(1-12) was undetectable. In renin knockout mice, all angiotensins, including angiotensin-(1-12), were undetectable at all sites, despite a 50% rise in angiotensinogen. Angiotensin-(1-12) metabolism in human blood plasma was not affected by renin inhibition. Yet, blockade of angiotensin-converting enzyme and aminopeptidase A, but not of chymase, neutral endopeptidase, or prolyl oligopeptidase, prolonged the half-life of angiotensin-(1-12), and angiotensin-converting enzyme inhibition prevented the formation of angiotensin II.
CONCLUSIONS
We were unable to detect intact angiotensin-(1-12) in humans or mice, either in blood or tissue, suggesting that this metabolite is an unlikely source of endogenous angiotensins.
PubMed: 38716648
DOI: 10.1161/HYPERTENSIONAHA.124.22856 -
Clinical Proteomics Feb 2024Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify...
BACKGROUND
Hypertension is an important public health priority with a high prevalence in Africa. It is also an independent risk factor for kidney outcomes. We aimed to identify potential proteins and pathways involved in hypertension-associated albuminuria by assessing urinary proteomic profiles in black South African participants with combined hypertension and albuminuria compared to those who have neither condition.
METHODS
The study included 24 South African cases with both hypertension and albuminuria and 49 control participants who had neither condition. Protein was extracted from urine samples and analysed using ultra-high-performance liquid chromatography coupled with mass spectrometry. Data were generated using data-independent acquisition (DIA) and processed using Spectronaut™ 15. Statistical and functional data annotation were performed on Perseus and Cytoscape to identify and annotate differentially abundant proteins. Machine learning was applied to the dataset using the OmicLearn platform.
RESULTS
Overall, a mean of 1,225 and 915 proteins were quantified in the control and case groups, respectively. Three hundred and thirty-two differentially abundant proteins were constructed into a network. Pathways associated with these differentially abundant proteins included the immune system (q-value [false discovery rate] = 1.4 × 10), innate immune system (q = 1.1 × 10), extracellular matrix (ECM) organisation (q = 0.03) and activation of matrix metalloproteinases (q = 0.04). Proteins with high disease scores (76-100% confidence) for both hypertension and chronic kidney disease included angiotensinogen (AGT), albumin (ALB), apolipoprotein L1 (APOL1), and uromodulin (UMOD). A machine learning approach was able to identify a set of 20 proteins, differentiating between cases and controls.
CONCLUSIONS
The urinary proteomic data combined with the machine learning approach was able to classify disease status and identify proteins and pathways associated with hypertension-associated albuminuria.
PubMed: 38402394
DOI: 10.1186/s12014-024-09458-9 -
Scientific Reports Nov 2023It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen...
Hypothyroidism increases angiotensinogen gene expression associated with vascular smooth muscle cells cholesterol metabolism dysfunction and aorta remodeling in Psammomys obesus.
It has been previously shown that clinical cardiovascular manifestations can be caused by mild changes in thyroid function. However, the implication of angiotensinogen (Agt) and vascular smooth muscle cells (VSMCs) dysfunction in the pathophysiology of cardiovascular manifestations in hypothyroidism have not yet been investigated. We induced experimental hypothyroidism in Psammomys obesus by administering carbimazole for five months. At the end of the experiment, the animals were sacrificed and histopathological analysis was performed using Masson's trichrome staining of the aorta and thyroid gland. The expression of the Agt gene and the genes implicated in cholesterol metabolism regulation in the liver and VSMCs was determined by qRT-PCR. Histological observations revealed profound remodeling of the aorta structure in animals with hypothyroidism. In addition, Agt gene expression in the liver was significantly increased. In vitro study, showed that VSMCs from hypothyroid animals overexpressed 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and Acyl CoA:cholesterol acyltransferase (Acat) 1, with failure to increase the efflux pathway genes (ATP-binding cassette subfamily G member (Abcg) 1 and 4). These results suggest that hypothyroidism leads to vascular alterations, including structural remodeling, VSMCs cholesterol metabolism dysfunction, and their switch to a synthetic phenotype, together with hepatic Agt gene overexpression.
Topics: Animals; Gerbillinae; Muscle, Smooth, Vascular; Angiotensinogen; Cholesterol; Hypothyroidism; Aorta; Gene Expression; Myocytes, Smooth Muscle
PubMed: 37951959
DOI: 10.1038/s41598-023-46899-y -
Medicine Mar 2024Coronary artery disease (CAD) is the third most common cause of mortality globally (with 17.8 million deaths annually). Angiotensinogen (AGT) and polymorphisms in this...
Coronary artery disease (CAD) is the third most common cause of mortality globally (with 17.8 million deaths annually). Angiotensinogen (AGT) and polymorphisms in this gene can be considered as susceptibility factors for CAD. We performed a retrospective case-control study to determine the correlation of AGT rs5051 and rs699 polymorphisms with CAD in an Iranian population. We genotyped 310 CAD patients and 310 healthy subjects using polymerase chain reaction-based methods. To confirm the accuracy of the screening approach, 10% of genotyped subjects were validated using gold-standard Sanger Sequencing. To evaluate the effect of the candidate polymorphisms, white blood cells were randomly purified from the subjects and AGT expression was measured by quantitative reverse transcriptase-polymerase chain reaction. Sex stratification indicated a significant correlation between CAD and male sex (P = .0101). We found a significant association between the rs5051 A allele (P = .002) and the rs699 C allele, and CAD (P = .0122) in recessive and dominant models. Moreover, our findings showed a significant association of the haplotype, including the rs5051 A/A and rs699 T/C genotypes, with CAD (P = .0405). Finally, AGT mRNA levels were significantly decreased in patients harboring the candidate polymorphisms (P = .03). According to our findings The AGT rs5051 A and AGT rs699 C alleles are predisposing variants of CAD risk and severity in the Iranian population.
Topics: Humans; Male; Angiotensinogen; Case-Control Studies; Coronary Artery Disease; Gene Frequency; Genetic Predisposition to Disease; Genotype; Iran; Retrospective Studies; Risk Factors
PubMed: 38489704
DOI: 10.1097/MD.0000000000037045 -
Journal of Obstetrics and Gynaecology :... Dec 2023The aetiological mechanism of preeclampsia (PE) is unclear exactly, so we attempted to investigate the association between susceptibility to preeclampsia and... (Meta-Analysis)
Meta-Analysis
The aetiological mechanism of preeclampsia (PE) is unclear exactly, so we attempted to investigate the association between susceptibility to preeclampsia and renin-angiotensin-aldosterone system (RAAS) gene polymorphisms to explore the aetiology in terms of genetics. A systematic search was performed in electronic databases to identify relevant studies. Eventually 73 studies were enrolled, odds ratios were generated by 5 genetic models. In overall analysis, significant associations were detected for AGT M235T, AT1R A1166C and CYP11B2 C344T whereas negative correlation was shown for AGT T174M. As stratified by race and geography, AGT 235T allele and AT1R 1166C allele increased preeclampsia risk and AGT T174M was justified uncorrelated with preeclampsia. Our meta-analysis illustrated that AGT 235T allele and AT1R 1166C allele increased and CYP11B2 344T allele decreased preeclampsia risk while AGT T174M polymorphism did not change preeclampsia risk. Hence, pregnant women carrying high-risk genotypes need strengthened management to prevent and early identification of preeclampsia.
Topics: Female; Humans; Pregnancy; Renin-Angiotensin System; Pre-Eclampsia; Cytochrome P-450 CYP11B2; Angiotensinogen; Polymorphism, Genetic; Genotype; Genetic Predisposition to Disease
PubMed: 36718570
DOI: 10.1080/01443615.2023.2171782 -
SAGE Open Medical Case Reports 2023The majority of acute subdural hematomas are due to trauma, and cases of spontaneous subdural hematoma are rare. This report aims to provide an overview of subdural...
The majority of acute subdural hematomas are due to trauma, and cases of spontaneous subdural hematoma are rare. This report aims to provide an overview of subdural hematoma associated with COVID-19 virus. We described a case of a 22-year-old female without comorbidities and confirmed COVID-19 with spontaneous subdural hematoma on non-contrast computed tomography scan. This was the first case encountered in our hospital. There is no published cases yet in the Philippines. Mechanisms linking cerebrovascular events to COVID-19 are hypothesized. First, it has been postulated that COVID virus is neurotropic toward angiotensinogen-converting enzyme-2 receptors and it can invade and directly damage cerebral vessels. Second, entry of the virus into the cells results in marked reduction in angiotensinogen-converting enzyme-2 levels which could contribute to the development of intracranial hemorrhage. Third, COVID-19 patients usually develop a systemic hyperinflammatory syndrome characterized by fulminant hypercytokinemia which may mediate vascular remodeling and predispose to intracranial hemorrhage. COVID infection should be considered as one of the differentials in patients presenting with neurological symptom. More research needs to be performed to understand the pathogenic mechanisms behind each of these disorders and better treat such patients with suitable drugs in a timely manner.
PubMed: 37431489
DOI: 10.1177/2050313X231185951 -
Diabetes, Metabolic Syndrome and... 2024Hypertension is a leading cause of cardiovascular-related morbidity and mortality worldwide, with a prevalence increasing at an alarming rate in both middle- and...
PURPOSE
Hypertension is a leading cause of cardiovascular-related morbidity and mortality worldwide, with a prevalence increasing at an alarming rate in both middle- and low-income countries. Various environmental and genetic factors have been attributed to play a significant role in the increasing prevalence of hypertension. Single nucleotide polymorphisms (SNPs) in the angiotensinogen () gene are reported to have a significant association with hypertension; however, there are limited studies done on South African populations. Therefore, this case-control study aimed to investigate the association between SNPs (rs2004776, rs3789678, rs5051 and rs7079) with hypertension in a study population of isiXhosa-speaking participants from the Eastern Cape Province in South Africa.
MATERIALS AND METHODS
The SNPs were genotyped in 250 hypertensive cases and 237 normotensive controls, using TaqMan genotyping assays.
RESULTS
For the SNP rs2004776, the frequency of CC genotype (18.4%) and C allele (44%) in hypertensive cases showed no significant differences (p = 0.52, χ2 = 1.32), when compared to the normotensive control group (CC: 19.8% and C allele: 43%). Similar results were obtained for the genotypic and allelic frequencies between hypertensive cases and normotensive controls for rs3789678 (p = 0.88, χ2=0.26) and rs5051 (p = 0.57, χ2=1.12), and rs7079 (p = 0.33, χ2=2.23). These findings demonstrate that there were no significant associations between the SNPs rs2004776, rs3789678, rs7079, rs5051 with hypertension in our study population.
CONCLUSION
These findings suggest that gene polymorphisms are not associated with the development of hypertension in the studied population. The present study represents the first genetic report to investigate the gene polymorphisms with hypertension in an isiXhosa-speaking South African population.
PubMed: 38706806
DOI: 10.2147/DMSO.S452272