Abstract:
RATIONALE:Individuals with naturally occurring loss-of-function proprotein convertase subtilisin/kexin type 9 (PCSK9) mutations experience reduced low-density lipoprotein cholesterol levels and protection against cardiovascular disease. OBJECTIVE:The goal of this study was to assess whether genome editing using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system can efficiently introduce loss-of-function mutations into the endogenous PCSK9 gene in vivo. METHODS AND RESULTS:We used adenovirus to express CRISPR-associated 9 and a CRISPR guide RNA targeting Pcsk9 in mouse liver, where the gene is specifically expressed. We found that <3 to 4 days of administration of the virus, the mutagenesis rate of Pcsk9 in the liver was as high as >50%. This resulted in decreased plasma PCSK9 levels, increased hepatic low-density lipoprotein receptor levels, and decreased plasma cholesterol levels (by 35-40%). No off-target mutagenesis was detected in 10 selected sites. CONCLUSIONS:Genome editing with the CRISPR-CRISPR-associated 9 system disrupts the Pcsk9 gene in vivo with high efficiency and reduces blood cholesterol levels in mice. This approach may have therapeutic potential for the prevention of cardiovascular disease in humans.
journal_name
Circ Resjournal_title
Circulation researchauthors
Ding Q,Strong A,Patel KM,Ng SL,Gosis BS,Regan SN,Cowan CA,Rader DJ,Musunuru Kdoi
10.1161/CIRCRESAHA.115.304351subject
Has Abstractpub_date
2014-08-15 00:00:00pages
488-92issue
5eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.115.304351journal_volume
115pub_type
杂志文章abstract::The inward current ("oscillatory current") which may be present after the end of a depolarizing clamp was studied in sheep cardiac Purkinje fibers by means of a voltage-clamp method. The following results were obtained. In order to appear, the oscillatory current (Ios) requires a previous depolarization to approximate...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.48.5.618
更新日期:1981-05-01 00:00:00
abstract:RATIONALE:Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associate...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.308811
更新日期:2016-06-24 00:00:00
abstract::The purpose of this study was to examine by freeze-fracture the ultrastructure of intercellular junctions between mouse pulmonary endothelial and epithelial cells, and to relate this fine structure to that deduced from previous physiological and ultrastructural studies using tracer techniques. Junctions between capill...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.38.5.404
更新日期:1976-05-01 00:00:00
abstract::In our morphometric study of the effects of exercise on the heart, male Wistar-Kyoto rats at 5 weeks of age were subjected daily to a moderate treadmill running program that lasted for 7 weeks. The heart responded to physical conditioning by different magnitudes of tissue growth of the right (22%) and left (7%) ventri...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.52.1.57
更新日期:1983-01-01 00:00:00
abstract::Prolongation of the action potential has been postulated to be a major reason for the altered diastolic relaxation of the heart in patients with severe heart failure. To investigate the electrophysiological basis for this action potential prolongation in terminal heart failure, K+ currents were recorded in single vent...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.73.2.379
更新日期:1993-08-01 00:00:00
abstract::Cation channels activated by Ca(2+) store depletion have been proposed to mediate Ca(2+) influx in vascular smooth muscle cells. The aim of this study was to determine if store-operated channels have a functional role in pulmonary artery smooth muscle cells (PASMCs). In intact rat pulmonary artery rings, cyclopiazonic...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh2201.100315
更新日期:2001-11-09 00:00:00
abstract::Studies were performed to characterize the morphology and vascular reactivity of the allografted cerebral microcirculation. Cerebral cortical tissue was allografted into the cheek pouch of the hamster so that cerebral parenchymal vessels could be studied. The vascular morphology was characterized by a large number of ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.4.758
更新日期:1988-10-01 00:00:00
abstract::Triadin 1 (TRD) is an integral membrane protein that associates with the ryanodine receptor (RyR2), calsequestrin (CASQ2) and junctin to form a macromolecular Ca signaling complex in the cardiac junctional sarcoplasmic reticulum (SR). To define the functional role of TRD, we examined the effects of adenoviral-mediated...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000160609.98948.25
更新日期:2005-04-01 00:00:00
abstract::Hibernating myocardium, characterized by reductions in flow and function at rest, has limited contractile reserve in response to increases in external workload. We hypothesized that this attenuation of function reflects an adaptive downregulation that prevents the development of metabolic evidence of ischemia during s...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000049104.57549.03
更新日期:2003-01-10 00:00:00
abstract::Many cell types undergo apoptosis under conditions of ischemia. Little is known, however, about the molecular pathways that mediate this response. A cellular and biochemical approach to elucidate such signaling pathways was undertaken in primary cultures of cardiac myocytes, a cell type that is especially sensitive to...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.85.5.403
更新日期:1999-09-03 00:00:00
abstract:RATIONALE:Cryptogenic strokes, those of unknown cause, have been estimated as high as 30% to 40% of strokes. Inflammation has been suggested as a critical etiologic factor. However, there is lack of experimental evidence. OBJECTIVE:In this study, we investigated inflammation-associated stroke using a mouse model that ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.310349
更新日期:2017-12-08 00:00:00
abstract::We determined whether local bradykinin production modulates cardiac adrenergic activity. Depolarization of guinea pig heart sympathetic nerve endings (synaptosomes) with 1 to 100 mmol/L K+ caused the release of endogenous norepinephrine (10% to 50% above basal level). This release was exocytotic, because it depended o...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.5.774
更新日期:1997-11-01 00:00:00
abstract:RATIONALE:Although PSA (prostate-specific antigen)-a tumor marker for prostate cancer-has been reported to be associated with cardiovascular disease (CVD) risk factors, studies on the association of PSA with subclinical and clinical CVD remain limited. OBJECTIVE:We examined the association of total serum PSA within th...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.118.313413
更新日期:2019-05-10 00:00:00
abstract:RATIONALE:We previously reported that type VI collagen deposition increases in the infarcted myocardium in vivo. To date, a specific role for this nonfibrillar collagen has not been explored in the setting of myocardial infarction (MI). OBJECTIVE:To determine whether deletion of type VI collagen in an in vivo model of...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.252734
更新日期:2012-03-16 00:00:00
abstract::The influence of inhibition of the Na+ pump, with secondary stimulation of Na+-Ca++ exchange, on cellular Ca++ distribution is examined using the on-line scintillation disk technique and cultured neonatal rat myocardial cells. Under control conditions, La+++ displaced 78.1 +/- 1.13% (SEM) of the total cell associated ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.51.5.543
更新日期:1982-11-01 00:00:00
abstract::The atrioventricular (AV) node is a recurrent source of potentially life-threatening arrhythmias. Nevertheless, limited data are available on its developmental control or molecular phenotype. We used a novel AV nodal myocardium-specific reporter mouse to gain insight into the gene programs determining the formation an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.192443
更新日期:2009-07-02 00:00:00
abstract::The focal pattern of atherosclerotic lesions in arterial vessels suggests that local blood flow patterns are important factors in atherosclerosis. Although disturbed flows in the branches and curved regions are proatherogenic, laminar flows in the straight parts are atheroprotective. Results from in vitro studies on c...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.0000038487.19924.18
更新日期:2002-11-01 00:00:00
abstract::Pulsatile pulmonary hemodynamics were analyzed in a chronic awake canine high flow model. Standard mean flow and pulsatile flow hemodynamics were measured and alterations in the proximal pulmonary vascular physical properties were quantified by the characteristic impedance (Zo). Pulmonary vascular resistance (PVR), wh...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.45.2.267
更新日期:1979-08-01 00:00:00
abstract:RATIONALE:MicroRNAs modestly suppress their direct mRNA targets, and these direct effects are amplified by modulation of gene transcription pathways. Consequently, indirect mRNA modulatory effects of microRNAs to increase or decrease mRNAs greatly outnumber direct target suppressions. Because microRNAs are products of ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.300975
更新日期:2013-06-21 00:00:00
abstract:RATIONALE:Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear. OBJECTIVE:To determine how mitochond...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.301319
更新日期:2013-09-13 00:00:00
abstract::Clonidine and related drugs cause a specific pattern of cardiovascular depression by an agonistic effect on alpha-adrenoceptors within the central nervous system (CNS). For further characterization of the central adrenoceptors, the actions of three substances of the "clonidine-type" derived from two different chemical...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1980-06-01 00:00:00
abstract::To elucidate the local effects of renin in the coronary circulation, we examined local angiotensin (Ang) I and II formation, as well as coronary vasoconstriction in response to renin administration, and compared the effects with exogenous infused Ang I. We perfused isolated hearts from rats overexpressing the human an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.82.1.13
更新日期:1998-01-09 00:00:00
abstract:RATIONALE:Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translat...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.307017
更新日期:2016-01-22 00:00:00
abstract::We have recently demonstrated that endogenous erythropoietin (Epo)/Epo receptor (EpoR) system plays an important protective role in hypoxia-induced pulmonary hypertension. However, it remains to be examined whether vascular EpoR system contributes to angiogenesis in response to ischemia. We examined angiogenesis in Ep...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000260179.43672.fe
更新日期:2007-03-16 00:00:00
abstract:RATIONALE:The low-density lipoprotein (LDL) receptor (LDLR) is a central determinant of circulating LDL-cholesterol and as such subject to tight regulation. Recent studies and genetic evidence implicate the inducible degrader of the LDLR (IDOL) as a regulator of LDLR abundance and of circulating levels of LDL-cholester...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.115.307298
更新日期:2016-02-05 00:00:00
abstract::To determine whether or not salt loading restricted to the brain would elevate blood pressure, chronically implanted osmotic minipumps were used to infuse hypertonic sodium chloride solutions made in artificial cerebrospinal fluid into a jugular vein intravenously or the third cerebral ventricle, intracerebroventricul...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.54.5.566
更新日期:1984-05-01 00:00:00
abstract::We hypothesized that both acute and chronic accumulation of myocardial interstitial edema (extravascular fluid [EVF]) would compromise cardiac function. We also postulated that excess fluid within the myocardial interstitial space would potentiate interstitial fibrosis, thus further compromising function. Dogs were di...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.6.1713
更新日期:1991-06-01 00:00:00
abstract::Focal ectopic activity in cardiac tissue is a key factor in the initiation and perpetuation of tachyarrhythmias. Because myofibroblasts as present in fibrotic remodeled myocardia and infarct scars depolarize cardiomyocytes by heterocellular electrotonic interactions via gap junctions in vitro, we investigated using st...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.107.160549
更新日期:2007-10-12 00:00:00
abstract::Monocyte chemoattractant protein-1 (MCP-1) stimulates the formation of a collateral circulation on arterial occlusion. The present study served to determine whether these proarteriogenic properties of MCP-1 are preserved in hyperlipidemic apolipoprotein E-deficient (apoE-/-) mice and whether it affects the systemic de...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.0000052313.23087.3f
更新日期:2003-02-07 00:00:00
abstract::Obesity results in marked alterations in cardiac energy metabolism, with a prominent effect being an increase in fatty acid uptake and oxidation by the heart. Obesity also results in dramatic changes in the release of adipokines, such as leptin and adiponectin, both of which have emerged as important regulators of car...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.107.150417
更新日期:2007-08-17 00:00:00