Caldesmon- dependent switching between capillary endothelial cell growth and apoptosis through modulation of cell shape and contractility.

Abstract Caldesmon (CaD), a protein component of the actomyosin filament apparatus, modulates cell shape and cytoskeletal structure when overexpressed. When capillary endothelial cells were infected with an adenoviral vector encoding GFP-CaD under Tet-Off control, progressive inhibition of contractility, loss of actin stress fibers, disassembly of focal adhesions, and cell retraction resulted. This was accompanied by a cell shape (rounding)-dependent increase in apoptosis and concomitant inhibition of cell cycle progression. Cell growth also was inhibited in low expressor cells in which cell tension was suppressed independently of significant changes in cell shape, cytoskeletal structure, or focal adhesions. Thus, changes in both cytoskeletal structure and contractility appear to be central to the mechanism by which extracellular matrix-dependent changes in capillary cell shape influence growth and apoptosis during angiogenesis, and hence the cytoskeleton may represent a potential target for antiangiogenesis therapy

Therapeutic angiogenesis by transplantation of induced pluripotent stem cell-derived Flk-1 positive cells

<p>Abstract</p> <p>Background</p> <p>Induced pluripotent stem (iPS) cells are the novel stem cell population induced from somatic cells. It is anticipated that iPS will be used in the expanding field of regenerative medicine. Here, we investigated whether implantation of fetal liver kinase-1 positive (Flk-1⁺) cells derived from iPS cells could improve angiogenesis in a mouse hind limb model of ischemia.</p> <p>Results</p> <p>Flk-1⁺cells were induced from iPS cells after four to five days of culture. Hind limb ischemia was surgically induced and sorted Flk-1⁺cells were directly injected into ischemic hind limbs of athymic nude mice. Revascularization of the ischemic hind limb was accelerated in mice that were transplanted with Flk-1⁺cells compared with control mice, which were transplanted with vehicle, as evaluated by laser Doppler blood flowmetry. Transplantation of Flk-1⁺cells also increased expression of VEGF mRNA in ischemic tissue compared to controls.</p> <p>Conclusions</p> <p>Direct local implantation of iPS cell-derived Flk-1⁺cells would salvage tissues from ischemia. These data indicate that iPS cells could be valuable in the therapeutic induction of angiogenesis.</p

Omentin Prevents Myocardial Ischemic Injury Through AMP-Activated Protein Kinase- and Akt-Dependent Mechanisms

ObjectivesThis study examined the impact of omentin on myocardial injury in a mouse model of ischemia/reperfusion (I/R) and explored its underlying mechanisms.BackgroundObesity is a major risk factor for ischemic heart disease. Omentin is a circulating adipokine that is down-regulated by obesity.MethodsIn patients who underwent successful reperfusion treatment after acute myocardial infarction, cardiac function and perfusion defect were assessed by using scintigraphic images. Mice were subjected to myocardial ischemia followed by reperfusion.ResultsThis study found that high levels of plasma omentin were associated with improvement of heart damage and function after reperfusion therapy in patients with acute myocardial infarction. Systemic administration of human omentin to mice led to a reduction in myocardial infarct size and apoptosis after I/R, which was accompanied by enhanced phosphorylation of AMP-activated protein kinase (AMPK) and Akt in the ischemic heart. Fat-specific overexpression of human omentin also resulted in reduction of infarct size after I/R. Blockade of AMPK or Akt activity reversed omentin-induced inhibition of myocardial ischemic damage and apoptosis in mice. In cultured cardiomyocytes, omentin suppressed hypoxia/reoxygenation-induced apoptosis, which was blocked by inactivation of AMPK or Akt.ConclusionsOur data indicate that omentin functions as an adipokine that ameliorates acute ischemic injury in the heart by suppressing myocyte apoptosis through both AMPK- and Akt-dependent mechanisms

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation