Plasmalemma Vesicle-Associated Protein Has a Key Role in Blood-Retinal Barrier Loss.

Loss of blood-retinal barrier (BRB) properties induced by vascular endothelial growth factor (VEGF) and other factors is an important cause of diabetic macular edema. Previously, we found that the presence of plasmalemma vesicle-associated protein (PLVAP) in retinal capillaries associates with loss of BRB properties and correlates with increased vascular permeability in diabetic macular edema. In this study, we investigated whether absence of PLVAP protects the BRB from VEGF-induced permeability.

EUK-8, a superoxide dismutase and catalase mimetic, reduces cardiac oxidative stress and ameliorates pressure overload-induced heart failure in the harlequin mouse mutant.

Objectives: The purpose of this study was to identify apoptosis-inducing factor (AIF) as a cardiac mitochondrial antioxidant and assess the efficacy of EUK-8, a salen-manganese catalytic free radical scavenger, to protect the AIF-deficient myocardium against pressure overload.

Background: Oxidative stress has been postulated to provoke cell death and pathologic remodeling in heart failure. We recently characterized the apoptosis-inducing factor-deficient harlequin (Hq) mouse mutant to display excessive pressure overload-induced oxidative stress, cell death, accelerated progression to heart failure, and a reduced capacity of subsarcolemmal mitochondria to scavenge free radicals, suggesting a role for AIF as a novel mitochondrial antioxidant.

FGF6 in myogenesis.

Important functions in myogenesis have been proposed for FGF6, a member of the fibroblast growth factor family accumulating almost exclusively in the myogenic lineage. However, the analyses of Fgf6 (-/-) mutant mice gave contradictory results and the role of FGF6 during myogenesis remained largely unclear. Recent reports support the concept that FGF6 has a dual function in muscle regeneration, stimulating myoblast proliferation/migration and muscle differentiation/hypertrophy in a dose-dependent manner.

Downregulation of apoptosis-inducing factor in harlequin mutant mice sensitizes the myocardium to oxidative stress-related cell death and pressure overload-induced decompensation.

Apoptosis-inducing factor (AIF), or programmed cell death 8 (Pdcd8), is a highly conserved, ubiquitous flavoprotein localized in the mitochondrial intermembrane space. In vivo, AIF provides protection against neuronal apoptosis induced by oxidative stress. Conversely, in vitro, AIF has been demonstrated to have a proapoptotic role when, on induction of the mitochondrial death pathway, AIF translocates to the nucleus where it facilitates chromatin condensation and large scale DNA fragmentation.

Myocyte apoptosis in heart failure.

Human heart failure is preceded by a process termed cardiac remodeling in which heart chambers progressively enlarge and contractile function deteriorates. Programmed cell death (apoptosis) of cardiac muscle cells has been identified as an essential process in the progression to heart failure. The execution of the apoptotic program entails complex interactions between and execution of multiple molecular subprograms.

Myocyte hypertrophy and apoptosis: a balancing act.

In response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress the heart responds by enlarging the individual myofibers. Even though myocardial hypertrophy can normalize wall tension, it instigates an unfavorable outcome and threatens affected patients with sudden death or progression to overt heart failure, suggesting that in most instances hypertrophy is a maladaptive process. Increasing evidence suggests that several of the signaling cascades controlling myocyte growth in the adult heart also function to enhance survival of the myocyte population in response to pleiotropic death stimuli.

MCIP1 overexpression suppresses left ventricular remodeling and sustains cardiac function after myocardial infarction.

Pathological remodeling of the left ventricle (LV) after myocardial infarction (MI) is a major cause of heart failure. Although cardiac hypertrophy after increased loading conditions has been recognized as a clinical risk factor for human heart failure, it is unknown whether post-MI hypertrophic remodeling of the myocardium is beneficial for cardiac function over time, nor which regulatory pathways play a crucial role in this process. To address these questions, transgenic (TG) mice engineered to overexpress modulatory calcineurin-interacting protein-1 (MCIP1) in the myocardium were used to achieve cardiac-specific inhibition of calcineurin activation.