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 PURPOSE:Recent 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. METHODS:A 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. RESULTS:Major 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). CONCLUSION:Diastolic 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: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.
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