-
Hypertension Research : Official... Aug 2023Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of... (Review)
Review
Preeclampsia is a hypertensive disorder in pregnancy characterized by placental malperfusion and subsequent multi-organ injury. It accounts for approximately 14% of maternal deaths and 10-25% of perinatal deaths globally. In addition, preeclampsia has been attracting attentions for its association with risks for developing chronic diseases in later life for both mother and child. This mini-review discusses on latest knowledge on prediction, prevention, management, and long-term outcomes of preeclampsia and also touches on association between COVID-19 and preeclampsia. HTN hypertension, HDP hypertensive disorders of pregnancy, PE preeclampsia, BP blood pressure, cfDNA cell-free DNA, ST2 human suppression of tumorigenesis 2, sFlt-1 soluble fms-like tyrosine kinase-1, PIGF placental growth factor, VEGF vascular endothelial growth factor, VEGFR VEGF receptor, TGFβ transforming growth factor β, ENG endoglin, sENG soluble ENG, PRES posterior reversible encephalopathy syndrome, AKI acute kidney injury, CVD cardiovascular disease, ESKD end-stage kidney disease, ACE angiotensinogen converting enzyme, Ang angiotensin.
Topics: Female; Humans; Pregnancy; Biomarkers; COVID-19; Endoglin; Hypertension; Placenta; Placenta Growth Factor; Posterior Leukoencephalopathy Syndrome; Pre-Eclampsia; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1
PubMed: 37268721
DOI: 10.1038/s41440-023-01323-w -
Hypertension (Dallas, Tex. : 1979) May 2024The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes,... (Review)
Review
The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT receptor have opposing effects to the classical AT receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.
Topics: Angiotensin I; Angiotensin II; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Humans
PubMed: 38362781
DOI: 10.1161/HYPERTENSIONAHA.123.21364 -
Brain Communications 2023Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors...
Alzheimer's disease is a multifactorial disorder with large heterogeneity. Comorbidities such as hypertension, hypercholesterolaemia and diabetes are known contributors to disease progression. However, less is known about their mechanistic contribution to Alzheimer's pathology and neurodegeneration. The aim of this study was to investigate the relationship of several biomarkers related to risk mechanisms in Alzheimer's disease with the well-established Alzheimer's disease markers in a memory clinic population without common comorbidities. We investigated 13 molecular markers representing key mechanisms underlying Alzheimer's disease pathogenesis in CSF from memory clinic patients without diagnosed hypertension, hypercholesterolaemia or diabetes nor other neurodegenerative disorders. An analysis of covariance was used to compare biomarker levels between clinical groups. Associations were analysed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were analysed by immunofluorescence staining in the hippocampus of non-demented control and Alzheimer's disease individuals. CSF samples from a total of 90 participants were included in this study: 30 from patients with subjective cognitive decline (age 62.4 ± 4.38, female 60%), 30 with mild cognitive impairment (age 65.6 ± 7.48, female 50%) and 30 with Alzheimer's disease (age 68.2 ± 7.86, female 50%). Angiotensinogen, thioredoxin-1 and interleukin-15 had the most prominent associations with Alzheimer's disease pathology, synaptic and axonal damage markers. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer's disease patients. Grouping biomarkers by biological function showed that inflammatory and survival components were associated with Alzheimer's disease pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In the data-driven analysis, two patient clusters were identified: Cluster 1 had increased CSF markers of oxidative stress, vascular pathology and neuroinflammation and was characterized by elevated synaptic and axonal damage, compared with Cluster 2. Clinical groups were evenly distributed between the clusters. An analysis of post-mortem hippocampal tissue showed that compared with non-demented controls, angiotensinogen staining was higher in Alzheimer's disease and co-localized with phosphorylated-tau. The identification of biomarker-driven endophenotypes in cognitive disorder patients further highlights the biological heterogeneity of Alzheimer's disease and the importance of tailored prevention and treatment strategies.
PubMed: 37680670
DOI: 10.1093/braincomms/fcad228 -
International Journal of Molecular... Dec 2023Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through... (Review)
Review
Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases.
Topics: Humans; Aged; Cardiovascular Diseases; Proprotein Convertase 9; Heart Failure; Hypertension; RNA, Small Interfering; Atherosclerosis; RNA, Messenger
PubMed: 38203499
DOI: 10.3390/ijms25010328 -
Arteriosclerosis, Thrombosis, and... Dec 2023Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or... (Review)
Review
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent -acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Topics: Humans; Acetylgalactosamine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering
PubMed: 37855126
DOI: 10.1161/ATVBAHA.123.319897 -
The Canadian Journal of Cardiology Dec 2023Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence,... (Review)
Review
Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive drugs acting on new targets to improve control of blood pressure. This review discusses novel insights (including the data of recent clinical trials) with regard to interference with the renin-angiotensin system, focusing on the enzymes aminopeptidase A and angiotensin-converting enzyme 2 (ACE2) in the brain, as well as the substrate of renin- angiotensinogen-in the liver. It raises the possibility that centrally acting amino peptidase A inhibitors (eg, firibastat), preventing the conversion of angiotensin II to angiotensin III in the brain, might be particularly useful in African Americans and patients with obesity. Firibastat additionally upregulates brain ACE2, allowing the conversion of angiotensin II to its protective metabolite angiotensin-(1-7). Furthermore, antisense oligonucleotides or small interfering ribonucleic acids suppress hepatic angiotensinogen for weeks to months after 1 injection and thus could potentially overcome adherence issues. Finally, interference with ACE2 ubiquitination is emerging as a future option for the treatment of neurogenic hypertension, given that ubiquitination resistance might upregulate ACE2 activity.
Topics: Humans; Renin-Angiotensin System; Antihypertensive Agents; Glutamyl Aminopeptidase; Angiotensin-Converting Enzyme 2; Angiotensinogen; Angiotensin II; Hypertension; Brain
PubMed: 37348757
DOI: 10.1016/j.cjca.2023.06.013 -
Chronic Diseases and Translational... Jun 2024Hypertension (HTN) involves genetic variability in the renin-angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen ()...
BACKGROUND
Hypertension (HTN) involves genetic variability in the renin-angiotensin system and influences antihypertensive response. We previously reported that angiotensinogen () messenger RNA (mRNA) is endogenously bound by miR-122-5p and rs699 A > G decreases reporter mRNA in the microRNA functional-assay PASSPORT-seq. The promoter variant rs5051 C > T is in linkage disequilibrium (LD) with rs699 A > G and increases transcription. The independent effect of these variants is understudied due to their LD therefore we aimed to test the hypothesis that increased by rs5051 C > T counterbalances decreased by rs699 A > G, and when these variants occur independently, it translates to HTN-related phenotypes.
METHODS
We used in silico, in vitro, in vivo, and retrospective models to test this hypothesis.
RESULTS
In silico, rs699 A > G is predicted to increase miR-122-5p binding affinity by 3%. Mir-eCLIP results show rs699 is 40-45 nucleotides from the strongest microRNA-binding site in the mRNA. Unexpectedly, rs699 A > G increases mRNA in an -plasmid-cDNA HepG2 expression model. Genotype-Tissue Expression (GTEx) and UK Biobank analyses demonstrate liver expression and HTN phenotypes are not different when rs699 A > G occurs independently from rs5051 C > T. However, GTEx and the in vitro experiments suggest rs699 A > G confers cell-type-specific effects on mRNA abundance, and suggest paracrine renal renin-angiotensin-system perturbations could mediate the rs699 A > G associations with HTN.
CONCLUSIONS
We found that rs5051 C > T and rs699 A > G significantly associate with systolic blood pressure in Black participants in the UK Biobank, demonstrating a fourfold larger effect than in White participants. Further studies are warranted to determine if altered antihypertensive response in Black individuals might be due to rs5051 C > T or rs699 A > G. Studies like this will help clinicians move beyond the use of race as a surrogate for genotype.
PubMed: 38872760
DOI: 10.1002/cdt3.103