Inhibition of 2-AG hydrolysis differentially regulates blood brain barrier permeability after injury.

Background: Acute neurological insults caused by infection, systemic inflammation, ischemia, or traumatic injury are often associated with breakdown of the blood-brain barrier (BBB) followed by infiltration of peripheral immune cells, cytotoxic proteins, and water. BBB breakdown and extravasation of these peripheral components into the brain parenchyma result in inflammation, oxidative stress, edema, excitotoxicity, and neurodegeneration. These downstream consequences of BBB dysfunction can drive pathophysiological processes and play a substantial role in the morbidity and mortality of acute and chronic neurological insults, and contribute to long-term sequelae.

Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity.

Prominent cerebral amyloid angiopathy is often observed in the brains of elderly individuals and is almost universally found in patients with Alzheimer's disease. Cerebral amyloid angiopathy is characterized by accumulation of the shorter amyloid-β isoform(s) (predominantly amyloid-β40) in the walls of leptomeningeal and cortical arterioles and is likely a contributory factor to vascular dysfunction leading to stroke and dementia in the elderly. We used transgenic mice with prominent cerebral amyloid angiopathy to investigate the ability of ponezumab, an anti-amyloid-β40 selective antibody, to attenuate amyloid-β accrual in cerebral vessels and to acutely restore vascular reactivity.

A dysregulated endocannabinoid-eicosanoid network supports pathogenesis in a mouse model of Alzheimer's disease.

Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD). Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question.

Regional distribution of mitochondrial dysfunction and apoptotic remodeling in pacing-induced heart failure.

Background: Specific myocardial mitochondrial enzymatic dysfunction and apoptotic remodeling occur in pacing-induced heart failure. We sought to define their regional distribution and molecular basis in the failing heart.

Methods And Results: Enzyme dysfunction was assessed in mitochondrial subpopulations and immunoblot analysis was performed using homogenate proteins from the left atria (LA) and left ventricle (LV) of paced and control mongrel dogs.

Mitochondrial channelopathies in aging.

Defects in ion channels (channelopathies) are increasingly found in a large spectrum of human pathologies including aging. Mutations in genes encoding ion channel proteins, which disrupt channel function, are the most commonly identified cause of channelopathies. Mutations in associated proteins, alterations in the expression of ion channels, or changes in the activity of non-mutated channel genes or associated proteins can also produce acquired channelopathies.

Mitochondrial involvement in IGF-1 induced protection of cardiomyocytes against hypoxia/reoxygenation injury.

Studies in animal models of myocardial ischemia-reperfusion revealed that the administration of insulin-like growth factor (IGF-1) can provide substantial cardioprotective effect. However, the mechanisms by which IGF-1 prevents myocardial ischemia-reperfusion injury are not fully understood. This study addresses whether mitochondrial bioenergetic pathways are involved in the cardioprotective effects of IGF-1.

Mitochondrial-nuclear cross-talk in the aging and failing heart.

Hypothesis: Damage to heart mitochondrial structure and function occur with aging, and in heart failure (HF). However, the extent of mitochondrial dysfunction, the expression of mitochondrial and nuclear genes, and their cross-talk is not known.

Observations: Several observations have suggested that somatic mutations in mitochondrial DNA (mtDNA), induced by reactive oxygen species (ROS), appear to be the primary cause of energy decline, and that the generation of ROS is mainly the product of the mitochondrial respiratory chain.

Paradoxical cellular Ca2+ signaling in severe but compensated canine left ventricular hypertrophy.

In conscious dogs with severe left ventricular (LV) hypertrophy (H) (doubling of LV/body weight), which developed gradually over 1 to 2 years after aortic banding, baseline LV function was well compensated. The LV was able to generate twice the LV systolic pressure without an increase in LV end-diastolic pressure, or decrease in LV dP/dt or LV wall thickening. However, LV myocytes isolated from LVH dogs exhibited impaired contraction at baseline and in response to Ca2+.

Localization of functional endothelin receptor signaling complexes in cardiac transverse tubules.

Endothelin-1 (ET-1) is an autocrine factor in the mammalian heart important in enhancing cardiac performance, protecting against myocardial ischemia, and initiating the development of cardiac hypertrophy. The ETA receptor is a seven-transmembrane G-protein-coupled receptor whose precise subcellular localization in cardiac muscle is unknown. Here we used fluorescein ET-1 and 125I-ET-1 to provide evidence for ET-1 receptors in cardiac transverse tubules (T-tubules).

Protein kinase C and A sites on troponin I regulate myofilament Ca2+ sensitivity and ATPase activity in the mouse myocardium.

Cardiac troponin I (cTnI) is a phosphoprotein subunit of the troponin-tropomyosin complex that is thought to inhibit cardiac muscle contraction during diastole. To investigate the contributions of cTnI phosphorylation to cardiac regulation, transgenic mice were created with the phosphorylation sites of cTnI mutated to alanine. Activation of protein kinase C (PKC) by perfusion of hearts with phorbol-12-myristate-13-acetate (PMA) or endothelin-1 (ET-1) inhibited the maximum ATPase rate by up to 25 % and increased the Ca2+ sensitivity of ATPase activity and of isometric tension by up to 0.

Phosphorylation of troponin I controls cardiac twitch dynamics: evidence from phosphorylation site mutants expressed on a troponin I-null background in mice.

The cardiac myofilament protein troponin I (cTnI) is phosphorylated by protein kinase C (PKC), a family of serine/threonine kinases activated within heart muscle by a variety of agonists. cTnI is also a substrate for cAMP-dependent protein kinase (PKA) activated during beta-adrenergic signaling. To investigate the role of cTnI phosphorylation in contractile regulation by these pathways, we generated transgenic mice harboring a mutated cTnI protein lacking phosphorylation sites for PKC (serine(43/45) and threonine(144) mutated to alanine) and for PKA (serine(23/24) mutated to alanine).