CNS regulation of plasma cholesterol.

The incidence of disorders related to the control of energy homeostasis, such as hypertension, diabetes, obesity, and dyslipidemia, has dramatically increased worldwide in the last decades. The central nervous system (CNS) plays a critical role regulating the energy balance, therefore there has been increasing interest in understanding the mechanisms whereby the brain controls peripheral metabolism, in order to develop new potential therapies to treat those disorders. While the involvement of the CNS in development of hypertension, obesity, and diabetes has been thoroughly investigated, less is known about the specific role of the brain in the control of circulating lipids.

De novo cardiomyocytes from within the activated adult heart after injury.

A significant bottleneck in cardiovascular regenerative medicine is the identification of a viable source of stem/progenitor cells that could contribute new muscle after ischaemic heart disease and acute myocardial infarction. A therapeutic ideal--relative to cell transplantation--would be to stimulate a resident source, thus avoiding the caveats of limited graft survival, restricted homing to the site of injury and host immune rejection. Here we demonstrate in mice that the adult heart contains a resident stem or progenitor cell population, which has the potential to contribute bona fide terminally differentiated cardiomyocytes after myocardial infarction.

Enhancing AMPK activation during ischemia protects the diabetic heart against reperfusion injury.

AMPK activation during ischemia helps the myocardium to cope with the deficit of energy production. As AMPK activity is considered to be impaired in diabetes, we hypothesized that enhancing AMPK activation during ischemia above physiological levels would protect the ischemic diabetic heart through AMPK activation and subsequent inhibition of mitochondrial permeability transition pore (mPTP) opening. Isolated perfused hearts from normoglycemic Wistar or diabetic Goto-Kakizaki (GK) rats (n ≥ 6/group) were subjected to 35 min of ischemia in the presence of 10, 20, and 40 μM of A-769662, a known activator of AMPK, followed by 120 min of reperfusion with normal buffer.

Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma.

High-density lipoproteins (HDLs) mediate cholesterol transport and protection from cardiovascular disease. Although synthetic HDLs have been studied for 30 years, the structures of human plasma-derived HDL and its major protein apolipoprotein apoA-I are unknown. We separated normal human HDL into five density subfractions and then further isolated those containing predominantly apoA-I (LpA-I).

Hepatic deficiency of low density lipoprotein receptor-related protein-1 reduces high density lipoprotein secretion and plasma levels in mice.

The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1(-/-)) mice displayed lower fasting plasma HDL cholesterol levels when compared with hLrp1(+/+) mice.

Failure of the adipocytokine, resistin, to protect the heart from ischemia-reperfusion injury.

Experimental studies have linked the adipocytokines with acute cardioprotection. Whether the adipocytokine, resistin, confers protection is, however, debatable. In the current study, the actions of resistin, administered at reperfusion, were investigated in in vivo and in vitro rodent and in vitro human models of myocardial ischemia-reperfusion (I/R) injury.

Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure.

The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation.

High density lipoprotein: it's not just about lipid transport anymore.

Plasma levels of high density lipoprotein cholesterol (HDL-C) have long been associated with protection against cardiovascular disease (CVD) in large populations. However, HDL-C has been significantly less useful for predicting CVD risk in individual patients. This has ignited a new debate on the merits of measuring HDL quantity versus quality in terms of protective potential.

Transgenic overexpression of HSP56 does not result in cardiac hypertrophy nor protect from ischaemia/reperfusion injury.

Heat shock proteins are known to be induced during and following different forms of cardiac stress. It has previously been shown that their expression is beneficial for the heart following trauma such as ischaemia-reperfusion (I/R) injury. Heat shock protein 56 (HSP56) belongs to the family of FK506-binding immunophilin proteins and is found in steroid receptor complexes, notably the glucocorticoid receptor.

Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations.

Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing.

Proteomic characterization of human plasma high density lipoprotein fractionated by gel filtration chromatography.

Plasma levels of high density lipoprotein cholesterol (HDL-C) are inversely proportional to the incidence of cardiovascular disease. Recent applications of modern proteomic technologies have identified upward of 50 distinct proteins associated with HDL particles with many of these newly discovered proteins implicating HDL in nonlipid transport processes including complement activation, acute phase response and innate immunity. However, almost all MS-based proteomic studies on HDL to date have utilized density gradient ultracentrifugation techniques for HDL isolation prior to analysis.

Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore.

Leptin-induced protection against myocardial ischemia-reperfusion (I/R) injury involves the activation of the reperfusion injury salvage kinase pathway, incorporating phosphatidylinositol 3-kinase-Akt/protein kinase B and p44/42 MAPK, and the inhibition of the mitochondrial permeability transition pore (MPTP). Recently published data indicate that the JAK/STAT signaling pathway, which mediates the metabolic actions of leptin, also plays a pivotal role in cardioprotection. Consequently, in the present study we considered the possibility that JAK/STAT signaling linked to the MPTP may be involved in modulating the cardioprotective actions of leptin.

High-Density Lipoprotein Proteomics: Identifying New Drug Targets and Biomarkers by Understanding Functionality.

Recent proteomics studies on human plasma high-density lipoprotein (HDL) have discovered up to 50 individual protein constituents. Many of these have known functions that vary surprisingly from the lipid transport roles commonly thought to mediate HDL's ability to protect from coronary artery disease. Given newly discovered roles in inflammation, protease inhibition, complement regulation, and innate immunity, many have begun to view HDL as a broad collection of distinct particle subfamilies, each distinguished by unique protein compositions and functions.

Endothelial mitochondria and heart disease.

The endothelium is vital to the proper functioning in the heart, in particular due to its production of nitric oxide (NO) which regulates vascular tone. Damage to the endothelium contributes to the development of atherosclerosis, and hence to possible myocardial infarction and subsequent heart failure. Like most cells, endothelial cells contain mitochondria, despite their having relatively little dependence on oxidative phosphorylation for ATP production.

Construction and evaluation of an anatomically correct multi-image modality compatible phantom for prostate cancer focal ablation.

Purpose: Focal therapy using lasers is emerging as an alternative strategy for prostate cancer treatment. However, to our knowledge no anatomically correct models are available to test imaging and ablation techniques. Animal models present ethical, anatomical and cost challenges.

Estradiol increases the anorectic effect of central apolipoprotein A-IV.

Estrogens have potent suppressive effects on food intake and body weight in many species, including humans. Compelling evidence suggests estrogen's anorectic action is through an indirect mechanism by enhancing the strength of other physiological signals that reduce meal size such as apolipoprotein A-IV (apo A-IV), a satiation factor from the gut and brain. We determined whether estradiol, the primary form of estrogen, modulates the anorectic effect of apo A-IV.

Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.

Background: Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury.

Methods And Results: In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1).

Mitochondrial cyclophilin-D as a critical mediator of ischaemic preconditioning.

Aims: It has been suggested that mitochondrial reactive oxygen species (ROS), Akt and Erk1/2 and more recently the mitochondrial permeability transition pore (mPTP) may act as mediators of ischaemic preconditioning (IPC), although the actual interplay between these mediators is unclear. The aim of the present study is to determine whether the cyclophilin-D (CYPD) component of the mPTP is required by IPC to generate mitochondrial ROS and subsequently activate Akt and Erk1/2.

Methods And Results: Mice lacking CYPD (CYPD-/-) and B6Sv129 wild-type (WT) mice were used throughout.

Focal laser ablation for prostate cancer followed by radical prostatectomy: validation of focal therapy and imaging accuracy.

An increased incidence of low-risk prostate cancer (PCa) has led investigators to develop focal therapy as a management option for PCa. We evaluated the effects of focal laser ablation (FLA) on PCa tissue and the accuracy of magnetic resonance imaging (MRI) in determining ablated lesion volume by comparing the whole-mount histology and MRI in four patients that underwent FLA followed by radical prostatectomy. Ablated areas were characterized by homogeneous coagulation necrosis.

Real-time magnetic resonance imaging-guided focal laser therapy in patients with low-risk prostate cancer.

Two patients with low-risk prostate cancer (PCa) were treated with outpatient in-bore magnetic resonance imaging (MRI)-guided focal laser ablation. The tumor was identified on MRI. A laser fiber was delivered via a catheter inserted through a perineal template and guided to the target with MRI.

Transitory activation of AMPK at reperfusion protects the ischaemic-reperfused rat myocardium against infarction.

Purpose: AMPK plays a crucial role in the regulation of the energy metabolism of the heart. During ischaemia, AMPK activation is a known adaptative prosurvival mechanism that helps to maintain the energy levels of the myocardium. However, it still remains unclear if activation of AMPK during reperfusion is beneficial for the heart.

An evaluation of models for diotic and dichotic detection in reproducible noises.

Several psychophysical models for masked detection were evaluated using reproducible noises. The data were hit and false-alarm rates from three psychophysical studies of detection of 500-Hz tones in reproducible noise under diotic (N0S0) and dichotic (N0Spi) conditions with four stimulus bandwidths (50, 100, 115, and 2900 Hz). Diotic data were best predicted by an energy-based multiple-detector model that linearly combined stimulus energies at the outputs of several critical-band filters.