RNA editing of filamin A pre-mRNA regulates vascular contraction and diastolic blood pressure
Ontology highlight
ABSTRACT:
SUBMITTER: Prof. Michael, F Jantsch
PROVIDER: S-SCDT-EMBOJ-2016-94813 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:Epitranscriptomic events such as adenosine-to-inosine (A-to-I) RNA editing by ADAR can recode mRNAs to translate novel proteins. Editing of the mRNA that encodes actin crosslinking protein Filamin A (FLNA) mediates a Q-to-R transition in the interactive C-terminal region. While FLNA editing is conserved among vertebrates, its physiological function remains unclear. Here, we show that cardiovascular tissues in humans and mice show massive editing and that FLNA RNA is the most prominent substrate. Patient-derived RNA-Seq data demonstrate a significant drop in FLNA editing associated with cardiovascular diseases. Using mice with only impaired FLNA editing, we observed increased vascular contraction and diastolic hypertension accompanied by increased myosin light chain phosphorylation, arterial remodeling, and left ventricular wall thickening, which eventually causes cardiac remodeling and reduced systolic output. These results demonstrate a causal relationship between RNA editing and the development of cardiovascular disease indicating that a single epitranscriptomic RNA modification can maintain cardiovascular health.
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Project description:Background and purposeRecent clinical trials and expert consensus guidelines have typically focused on the issue of systolic blood pressure (SBP) targets for reducing vascular risk. However, little is known about the relationship of the diastolic BP (DBP) level with vascular outcomes after a stroke.MethodsA multicenter trial dataset involving 3680 recent (<4 months) non-cardioembolic stroke patients followed for 2 years was analyzed. Subjects were categorized per mean DBP level (mmHg) during follow-up: low-normal (<70), normal (70 to <80), high-normal (80-89) and high (≥90). Pulse pressure (PP) was prespecified by three categories of <60, 60 to <70, and ≥70 mmHg. Independent associations of mean DBP level with major vascular events (MVEs) and ischaemic stroke were assessed.ResultsMajor vascular events occurred in 20.7% of the low-normal, 15.1% of the normal, 16.9% of the high-normal and 19.2% of the high DBP groups, whilst stroke occurred in 9.9%, 6.8%, 8.5% and 10.8%, respectively. Compared with the normal DBP group, risk of MVEs was higher in the low-normal DBP group (adjusted hazard ratio 1.33; 95% confidence interval 1.04-1.71). Amongst those with SBP 120 to <140 mmHg, risk of MVEs (1.89; 1.13-3.15) and stroke (2.87; 1.48-5.53) was higher in subjects with PP ≥70 (mean DBP 62.4 ± 3.8) than those with the lowest PP (mean DBP 78.0 ± 5.9) whilst, amongst those with SBP <120 mmHg, PP 60 to <70 (mean DBP 52.7 ± 2.5) was associated with increased risk of stroke (5.85; 1.25-27.5).ConclusionDiastolic BP levels in the low-normal range, particularly accompanied by an increased PP of >60, confer increased risk of MVEs and stroke amongst patients after recent non-cardioembolic stroke.
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Project description:OBJECTIVES:High blood pressure (BP) is associated with diastolic dysfunction, but the consequence of elevated BP over the adult life course on diastolic function is unknown. We hypothesised that high BP in earlier adulthood would be associated with impaired diastolic function independent of current BP. METHODS:Participants in the Medical Research Council National Survey of Health and Development birth cohort (n=1653) underwent investigations including echocardiography at age 60-64?years. The relationships between adult BP, antihypertensive treatment (HTT) and echocardiographic measures of diastolic function were assessed using adjusted regression models. RESULTS:Increased systolic BP (SBP) at ages 36, 43 and 53?years was predictive of increased E/e' and increased left atrial volume. These effects were only partially explained by SBP at 60-64?years and increased left ventricular mass. HTT was also associated with poorer diastolic function after adjustment for SBP at 60-64?years. Faster rates of increase in SBP in midlife were also associated with increased poorer diastolic function. CONCLUSIONS:High SBP in midlife is associated with poorer diastolic function at age 60-64?years. Early identification of individuals with high BP or rapid rises in BP may be important for prevention of impaired cardiac function in later life.
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Project description:The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre). Wire myography performed on Cre-negative [wild-type (WT)] and Cre-positive (SM22α)CaSR(Δflox/Δflox) [knockout (KO)] mice showed an endothelium-independent reduction in aorta and mesenteric artery contractility of KO compared with WT mice in response to KCl and to phenylephrine. Increasing extracellular calcium ion (Ca(2+)) concentrations (1-5 mM) evoked contraction in WT but only relaxation in KO aortas. Accordingly, diastolic and mean arterial blood pressures of KO animals were significantly reduced compared with WT, as measured by both tail cuff and radiotelemetry. This hypotension was mostly pronounced during the animals' active phase and was not rescued by either nitric oxide-synthase inhibition with nitro-l-arginine methyl ester or by a high-salt-supplemented diet. KO animals also exhibited cardiac remodeling, bradycardia, and reduced spontaneous activity in isolated hearts and cardiomyocyte-like cells. Our findings demonstrate a role for CaSR in the cardiovascular system and suggest that physiologically relevant changes in extracellular Ca(2+) concentrations could contribute to setting blood vessel tone levels and heart rate by directly acting on the cardiovascular CaSR.
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Project description:BACKGROUND:The optimal systolic blood pressure (SBP) treatment goal is in question, with SPRINT (Systolic Blood Pressure Intervention Trial) suggesting benefit for 120 mm Hg. However, achieving an SBP this low may reduce diastolic blood pressure (DBP) to levels that could compromise myocardial perfusion. OBJECTIVES:This study sought to examine the independent association of DBP with myocardial damage (using high-sensitivity cardiac troponin-T [hs-cTnT]) and with coronary heart disease (CHD), stroke, or death over 21 years. METHODS:The authors studied 11,565 adults from the ARIC (Atherosclerosis Risk In Communities) cohort, analyzing DBP and hs-cTnT associations as well as prospective associations between DBP and events. RESULTS:Mean baseline age was 57 years, 57% of patients were female, and 25% were black. Compared with persons who had DBP between 80 to 89 mm Hg at baseline (ARIC visit 2), the adjusted odds ratio of having hs-cTnT ?14 ng/l at that visit was 2.2 and 1.5 in those with DBP <60 mm Hg and 60 to 69 mm Hg, respectively. Low DBP at baseline was also independently associated with progressive myocardial damage on the basis of estimated annual change in hs-cTnT over the 6 years between ARIC visits 2 and 4. In addition, compared with a DBP of 80 to 89 mm Hg, a DBP <60 mm Hg was associated with incident CHD and mortality, but not with stroke. The DBP and incident CHD association was strongest with baseline hs-cTnT ?14 ng/l (p value for interaction <0.001). Associations of low DBP with prevalent hs-cTnT and incident CHD were most pronounced among patients with baseline SBP ?120 mm Hg. CONCLUSIONS:Particularly among adults with an SBP ?120 mm Hg, and thus elevated pulse pressure, low DBP was associated with subclinical myocardial damage and CHD events. When titrating treatment to SBP <140 mm Hg, it may be prudent to ensure that DBP levels do not fall below 70 mm Hg, and particularly not below 60 mm Hg.
| S-EPMC5089057 | biostudies-literature
Project description:The identity of the specific nitric oxide dioxygenase (NOD) that serves as the main in vivo regulator of O2-dependent NO degradation in smooth muscle remains elusive. Cytoglobin (Cygb) is a recently discovered globin expressed in fibroblasts and smooth muscle cells with unknown function. Cygb, coupled with a cellular reducing system, efficiently regulates the rate of NO consumption by metabolizing NO in an O2-dependent manner with decreased NO consumption in physiological hypoxia. Here we show that Cygb is a major regulator of NO degradation and cardiovascular tone. Knockout of Cygb greatly prolongs NO decay, increases vascular relaxation, and lowers blood pressure and systemic vascular resistance. We further demonstrate that downregulation of Cygb prevents angiotensin-mediated hypertension. Thus, Cygb has a critical role in the regulation of vascular tone and disease. We suggest that modulation of the expression and NOD activity of Cygb represents a strategy for the treatment of cardiovascular disease.
| S-EPMC5394235 | biostudies-literature
Project description:In order to study the relationship of the patient's anxiety level from Corah's Dental Anxiety Scale (DAS) vs different physiological parameters: pre and post-operative blood pressure, and pre and post-operative heart rates, and subsequently, relate the results to the patient's post-operative anti-inflammatory analgesic need, 185 patients requiring a simple dental extraction were recruited. They filled out the DAS in the waiting room prior to their procedure and once in the examination room, their preoperative blood pressure and heart rate was measured. Once the dental extraction had been completed, their blood pressure and heart rate were measured again. Before leaving the clinic, the patient was given an analgesic form in which they had to indicate whether or not they had required analgesia after the procedure. Diastolic blood pressure (DBP) showed statistically significant differences between pre-operative and post-operative (P?=?0.001). DAS was related with pre-operative diastolic blood pressure (pre-DBP) (P?=?0.001) and post-operative diastolic blood pressure (post-DBP) as well as pre-operative heart rate (pre-HR) (P?=?0.027) and post-operative heart rate (post-HR) (P?=?0.013). Patients with high levels of DAS tend to take more Ibuprofen 400?mg (P?=?0.038). The different levels of anxiety will determine what type of anti-inflammatory analgesia the patient will take, if necessary.
| S-EPMC7280201 | biostudies-literature
Project description:Hypertension is a primary risk factor for cardiovascular diseases including myocardial infarction and stroke. Major determinants of blood pressure are vasodilatory factors such as nitric oxide (NO) released from the endothelium under the influence of fluid shear stress exerted by the flowing blood. Several endothelial signaling processes mediating fluid shear stress-induced formation and release of vasodilatory factors have been described. It is, however, still poorly understood how fluid shear stress induces these endothelial responses. Here we show that the endothelial mechanosensitive cation channel PIEZO1 mediated fluid shear stress-induced release of adrenomedullin, which in turn activated its Gs-coupled receptor. The subsequent increase in cAMP levels promoted the phosphorylation of endothelial NO synthase (eNOS) at serine 633 through protein kinase A (PKA), leading to the activation of the enzyme. This Gs/PKA-mediated pathway synergized with the AKT-mediated pathways leading to eNOS phosphorylation at serine 1177. Mice with endothelium-specific deficiency of adrenomedullin, the adrenomedullin receptor, or Gαs showed reduced flow-induced eNOS activation and vasodilation and developed hypertension. Our data identify fluid shear stress-induced PIEZO1 activation as a central regulator of endothelial adrenomedullin release and establish the adrenomedullin receptor and subsequent Gs-mediated formation of cAMP as a critical endothelial mechanosignaling pathway regulating basal endothelial NO formation, vascular tone, and blood pressure.
| S-EPMC6597232 | biostudies-literature
Project description:AimsBlood pressure (BP) is a crucial factor in cardiovascular health and can affect cardiac imaging assessments. However, standard outpatient cardiovascular MR (CMR) imaging procedures do not typically include BP measurements prior to image acquisition. This study proposes that brachial systolic BP (SBP) and diastolic BP (DBP) can be modelled using patient characteristics and CMR data.MethodsIn this multicentre study, 57 patients from the PREFER-CMR registry and 163 patients from other registries were used as the derivation cohort. All subjects had their brachial SBP and DBP measured using a sphygmomanometer. Multivariate linear regression analysis was applied to predict brachial BP. The model was subsequently validated in a cohort of 169 healthy individuals.ResultsAge and left ventricular ejection fraction were associated with SBP. Aortic forward flow, body surface area and left ventricular mass index were associated with DBP. When applied to the validation cohort, the correlation coefficient between CMR-derived SBP and brachial SBP was (r=0.16, 95% CI 0.011 to 0.305, p=0.03), and CMR-derived DBP and brachial DBP was (r=0.27, 95% CI 0.122 to 0.403, p=0.0004). The area under the curve (AUC) for CMR-derived SBP to predict SBP>120 mmHg was 0.59, p=0.038. Moreover, CMR-derived DBP to predict DBP>80 mmHg had an AUC of 0.64, p=0.002.ConclusionCMR-derived SBP and DBP models can estimate brachial SBP and DBP. Such models may allow efficient prospective collection, as well as retrospective estimation of BP, which should be incorporated into assessments due to its critical effect on load-dependent parameters.
| S-EPMC10749049 | biostudies-literature
Project description:BackgroundIn individuals with a low diastolic blood pressure (DBP), the potential benefits or risks of intensive systolic blood pressure (SBP) lowering are unclear.MethodsSPRINT (Systolic Blood Pressure Intervention Trial) was a randomized controlled trial that compared the effects of intensive (target <120 mm Hg) and standard (target <140 mm Hg) SBP control in 9361 older adults with high blood pressure at increased risk of cardiovascular disease. The primary outcome was a composite of cardiovascular disease events. All-cause death and incident chronic kidney disease were secondary outcomes. This post hoc analysis examined whether the effects of the SBP intervention differed by baseline DBP.ResultsMean baseline SBP and DBP were 139.7±15.6 and 78.1±11.9 mm Hg, respectively. Regardless of the randomized treatment, baseline DBP had a U-shaped association with the hazard of the primary cardiovascular disease outcome. However, the effects of the intensive SBP intervention on the primary outcome were not influenced by baseline DBP level (P for interaction=0.83). The primary outcome hazard ratio for intensive versus standard treatment was 0.78 (95% confidence interval, 0.57-1.07) in the lowest DBP quintile (mean baseline DBP, 61±5 mm Hg) and 0.74 (95% confidence interval, 0.61-0.90) in the upper 4 DBP quintiles (mean baseline DBP, 82±9 mm Hg), with an interaction P value of 0.78. Results were similar for all-cause death and kidney events.ConclusionsLow baseline DBP was associated with increased risk of cardiovascular disease events, but there was no evidence that the benefit of the intensive SBP lowering differed by baseline DBP.Clinical trial registrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.
| S-EPMC5760457 | biostudies-literature