| 1. |
- Ahmadi, Amir, et al.
(författare)
-
Prognostic Determinants of Coronary Atherosclerosis in Stable Ischemic Heart Disease : Anatomy, Physiology, or Morphology?
- 2016
-
Ingår i: Circulation Research. - 0009-7330. ; 119:2, s. 317-329
-
Forskningsöversikt (refereegranskat)abstract
- Risk stratification in patients with stable ischemic heart disease is essential to guide treatment decisions. In this regard, whether coronary anatomy, physiology, or plaque morphology is the best determinant of prognosis (and driver an effective therapeutic risk reduction) remains one of the greatest ongoing debates in cardiology. In the present report, we review the evidence for each of these characteristics and explore potential algorithms that may enable a practical diagnostic and therapeutic strategy for the management of patients with stable ischemic heart disease.
|
|
| 2. |
- Arkelius, Kajsa, et al.
(författare)
-
LOX-1 and MMP-9 Inhibition Attenuates the Detrimental Effects of Delayed rt-PA Therapy and Improves Outcomes after Acute Ischemic Stroke
- 2024
-
Ingår i: Circulation Research. - 0009-7330. ; 134:8, s. 954-969
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acute ischemic stroke triggers endothelial activation that disrupts vascular integrity and increases hemorrhagic transformation leading to worsened stroke outcomes. rt-PA (recombinant tissue-type plasminogen activator) is an effective treatment; however, its use is limited due to a restricted time window and hemorrhagic transformation risk, which in part may involve activation of MMPs (matrix metalloproteinases) mediated through LOX-1 (lectin-like oxLDL [oxidized low-density lipoprotein] receptor 1). This study's overall aim was to evaluate the therapeutic potential of novel MMP-9 (matrix metalloproteinase 9) ± LOX-1 inhibitors in combination with rt-PA to improve stroke outcomes. METHODS: A rat thromboembolic stroke model was utilized to investigate the impact of rt-PA delivered 4 hours poststroke onset as well as selective MMP-9 (JNJ0966) ±LOX-1 (BI-0115) inhibitors given before rt-PA administration. Infarct size, perfusion, and hemorrhagic transformation were evaluated by 9.4-T magnetic resonance imaging, vascular and parenchymal MMP-9 activity via zymography, and neurological function was assessed using sensorimotor function testing. Human brain microvascular endothelial cells were exposed to hypoxia plus glucose deprivation/reperfusion (hypoxia plus glucose deprivation 3 hours/R 24 hours) and treated with ±tPA and ±MMP-9 ±LOX-1 inhibitors. Barrier function was assessed via transendothelial electrical resistance, MMP-9 activity was determined with zymography, and LOX-1 and barrier gene expression/levels were measured using qRT-PCR (quantitative reverse transcription PCR) and Western blot. RESULTS: Stroke and subsequent rt-PA treatment increased edema, hemorrhage, MMP-9 activity, LOX-1 expression, and worsened neurological outcomes. LOX-1 inhibition improved neurological function, reduced edema, and improved endothelial barrier integrity. Elevated MMP-9 activity correlated with increased edema, infarct volume, and decreased neurological function. MMP-9 inhibition reduced MMP-9 activity and LOX-1 expression. In human brain microvascular endothelial cells, LOX-1/MMP-9 inhibition differentially attenuated MMP-9 levels, inflammation, and activation following hypoxia plus glucose deprivation/R. CONCLUSIONS: Our findings indicate that LOX-1 inhibition and ± MMP-9 inhibition attenuate negative aspects of ischemic stroke with rt-PA therapy, thus resulting in improved neurological function. While no synergistic effect was observed with simultaneous LOX-1 and MMP-9 inhibition, a distinct interaction is evident.
|
|
| 3. |
- Arner, Anders, et al.
(författare)
-
Activation of contraction and ATPase activity in intact and chemically skinned smooth muscle of rat portal vein. Dependence on Ca++ and muscle length
- 1983
-
Ingår i: Circulation Research. - 0009-7330. ; 53:5, s. 695-702
-
Tidskriftsartikel (refereegranskat)abstract
- The mechanical manifestations of muscle contraction (force development or shortening) are accompanied by an increased turnover of chemical energy (ATPase activity, JATP). In intact rat portal veins activated by high potassium medium to produce graded contractions at different levels of extracellular calcium, a linear dependence of oxygen consumption on force was found. The slope of the relation (metabolic tension cost) was higher during early stages than during late stages of contraction, possibly reflecting a transient high crossbridge ATP turnover rate. Chemically skinned (Triton X-100) rat portal vein preparations were used to study the energy turnover of the smooth muscle contractile system under constant activation. In these preparations, JATP increased on activation by calcium in the presence of 1 microM calmodulin, remained constant for maintained contractures, and decreased promptly on relaxation. Force declined with each repeated contraction at optimal calcium level (10(-4.5) M), but the relation between force and JATP remained invariant and agreed with that of the intact muscle during the transient of high ATP turnover. Calcium activation in the range 10(-9) to 10(-4.5) M caused a progressively steeper (nonlinear) increase in JATP with force. Length-force relations showed a lower relative force at muscle lengths below L0 in the intact than in the skinned tissue, possibly indicating depression of excitation-contraction coupling. The slope of the relation between JATP and force was lower when length was varied than when calcium was varied. At a length where no external force was produced, the activated muscle had a significantly higher JATP than while relaxed (10(-9) M Ca++). Together with previous results showing calcium dependence of the force-velocity relation, the present study indicates an influence of calcium on crossbridge kinetics in smooth muscle.
|
|
| 4. |
- Arner, Anders, et al.
(författare)
-
Energy turnover and mechanical properties of resting and contracting aortas and portal veins from normotensive and spontaneously hypertensive rats
- 1981
-
Ingår i: Circulation Research. - 0009-7330. ; 48:4, s. 539-548
-
Tidskriftsartikel (refereegranskat)abstract
- Aortas and portal veins from spontaneously hypertensive rats (SHR) and matched normotensive Wistar-Kyoto rats (WKY) were studied with respect to their energy turnover and mechanical properties. Relaxed aortas fom SHR 16--17 weeks and 20--25 weeks of age were stiffer, had smaller circumference, and greater maximal active wall tension compared to WKY aortas. Active stress (forced/areas) was not different. Passive and active length-force relations of portal veins from 16 to 17-week-old SHR and WKY were not different. O2 consumption (JO2) and lactate production (JLA) were studied in aortas and portal veins from 20- to 25-week-old rats. In relaxed aortas, JO2 was 0.63 +/- 0.03 (n = 1) and 0.54 +/- 0.03 (n = 10) mu mol/min per g dry wt in SHR and WKY, respectively (P less than 0.05). On activation by high-K+ solution, JO2 increased with tension in a similar way in both groups. In contrast, JLA, about 0.85 mu mol/min per g, did not differ, and decreased with tension development. JO2 of relaxed portal veins, about 1.5 mu mol/min per g dry wt, and the increase in JO2 with contraction were not different between SHR and WKY, but the JO2-active stress relation was steeper in spontaneous activity than in Kv+ contractures. JLA was similar in SHR and WKY portal veins, about 1 mu mol/min per g, and unlike behavior of the aortas, it increased with tension. Thus it is evident that SHR show increased arterial metabolism, which is not accounted for by an increased energy demand of the contractile system.
|
|
| 5. |
- Arroz-Madeira, Silvia, et al.
(författare)
-
Lessons of Vascular Specialization From Secondary Lymphoid Organ Lymphatic Endothelial Cells
- 2023
-
Ingår i: Circulation Research. - : Wolters Kluwer. - 0009-7330 .- 1524-4571. ; 132:9, s. 1203-1225
-
Forskningsöversikt (refereegranskat)abstract
- Secondary lymphoid organs, such as lymph nodes, harbor highly specialized and compartmentalized niches. These niches are optimized to facilitate the encounter of naive lymphocytes with antigens and antigen-presenting cells, enabling optimal generation of adaptive immune responses. Lymphatic vessels of lymphoid organs are uniquely specialized to perform a staggering variety of tasks. These include antigen presentation, directing the trafficking of immune cells but also modulating immune cell activation and providing factors for their survival. Recent studies have provided insights into the molecular basis of such specialization, opening avenues for better understanding the mechanisms of immune-vascular interactions and their applications. Such knowledge is essential for designing better treatments for human diseases given the central role of the immune system in infection, aging, tissue regeneration and repair. In addition, principles established in studies of lymphoid organ lymphatic vessel functions and organization may be applied to guide our understanding of specialization of vascular beds in other organs.
|
|
| 6. |
- Aspelund, Aleksanteri, et al.
(författare)
-
Lymphatic System in Cardiovascular Medicine
- 2016
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 118:3, s. 515-530
-
Forskningsöversikt (refereegranskat)abstract
- The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system. In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction. Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease.
|
|
| 7. |
- Bergdahl, Andreas, et al.
(författare)
-
Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1.
- 2003
-
Ingår i: Circulation Research. - 0009-7330. ; 93:9, s. 839-847
-
Tidskriftsartikel (refereegranskat)abstract
- The reactivity of the vascular wall to endothelin-1 (ET-1) is influenced by cholesterol, which is of possible importance for the progression of atherosclerosis. To elucidate signaling steps affected, the cholesterol acceptor methyl-ß-cyclodextrin (mßcd, 10 mmol/L) was used to manipulate membrane cholesterol and disrupt caveolae in intact rat arteries. In endothelium-denuded caudal artery, contractile responsiveness to 10 nmol/L ET-1 (mediated by the ETA receptor) was reduced by mßcd and increased by cholesterol. Neither ligand binding nor colocalization of ETA and caveolin-1 was affected by mßcd. Ca2+ inflow via store-operated channels after depletion of intracellular Ca2+ stores was reduced in mßcd-treated caudal arteries, as shown by Mn2+ quench rate and intracellular [Ca2+] response. Expression of TRPC1, 3, and 6 was detected by reverse transcriptase–polymerase chain reaction, and colocalization of TRPC1 with caveolin-1 was reduced by mßcd, as seen by immunofluorescence. Part of the contractile response to ET-1 was inhibited by Ni2+ (0.5 mmol/L) and by a TRPC1 blocking antibody. In the basilar artery, exhibiting less store-operated channel activity than the caudal artery, ET-1–induced contractions were insensitive to the TRPC1 blocking antibody and to mßcd. Increased store-operated channel activity in basilar arteries after organ culture correlated with increased sensitivity of ET-1 contraction to mßcd. These results suggest that cholesterol influences vascular reactivity to ET-1 by affecting the caveolar localization of TRPC1.
|
|
| 8. |
- Bergmann, Olaf, et al.
(författare)
-
Cardiomyocyte Renewal in Humans
- 2012
-
Ingår i: Circulation Research. - 0009-7330 .- 1524-4571. ; 110:1, s. 17-18
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 9. |
- Bergmann, Olaf, et al.
(författare)
-
Turnover of Human Cardiomyocytes
- 2008
-
Ingår i: Circulation Research. - 0009-7330. ; 103:12, s. 1494-1495
-
Konferensbidrag (refereegranskat)
|
|
| 10. |
- Bertorello, Alejandro M., et al.
(författare)
-
Increased Arterial Blood Pressure and Vascular Remodeling in Mice Lacking Salt-Inducible Kinase 1 (SIK1)
- 2015
-
Ingår i: Circulation Research. - : American Heart Association. - 0009-7330 .- 1524-4571. ; 116:4, s. 642-U190
-
Tidskriftsartikel (refereegranskat)abstract
- Rationale: In human genetic studies a single nucleotide polymorphism within the salt-inducible kinase 1 (SIK1) gene was associated with hypertension. Lower SIK1 activity in vascular smooth muscle cells (VSMCs) leads to decreased sodium-potassium ATPase activity, which associates with increased vascular tone. Also, SIK1 participates in a negative feedback mechanism on the transforming growth factor-beta 1 signaling and downregulation of SIK1 induces the expression of extracellular matrix remodeling genes. Objective: To evaluate whether reduced expression/activity of SIK1 alone or in combination with elevated salt intake could modify the structure and function of the vasculature, leading to higher blood pressure. Methods and Results: SIK1 knockout (sik1(-/-)) and wild-type (sik1(+/+)) mice were challenged to a normal-or chronic high-salt intake (1% NaCl). Under normal-salt conditions, the sik1(-/-) mice showed increased collagen deposition in the aorta but similar blood pressure compared with the sik1(+/+) mice. During high-salt intake, the sik1+/+ mice exhibited an increase in SIK1 expression in the VSMCs layer of the aorta, whereas the sik1(-/-) mice exhibited upregulated transforming growth factor-beta 1 signaling and increased expression of endothelin-1 and genes involved in VSMC contraction, higher systolic blood pressure, and signs of cardiac hypertrophy. In vitro knockdown of SIK1 induced upregulation of collagen in aortic adventitial fibroblasts and enhanced the expression of contractile markers and of endothelin-1 in VSMCs. Conclusions: Vascular SIK1 activation might represent a novel mechanism involved in the prevention of high blood pressure development triggered by high-salt intake through the modulation of the contractile phenotype of VSMCs via transforming growth factor-beta 1-signaling inhibition.
|
|
