Hemodynamic Environments from Opposing Sides of Human Aortic Valve Leaflets Evoke Distinct Endothelial Phenotypes In Vitro

The regulation of valvular endothelial phenotypes by the hemodynamic environments of the human aortic valve is poorly understood. The nodular lesions of calcific aortic stenosis (CAS) develop predominantly beneath the aortic surface of the valve leaflets in the valvular fibrosa layer. However, the mechanisms of this regional localization remain poorly characterized. In this study, we combine numerical simulation with in vitro experimentation to investigate the hypothesis that the previously documented differences between valve endothelial phenotypes are linked to distinct hemodynamic environments characteristic of these individual anatomical locations. A finite-element model of the aortic valve was created, describing the dynamic motion of the valve cusps and blood in the valve throughout the cardiac cycle. A fluid mesh with high resolution on the fluid boundary was used to allow accurate computation of the wall shear stresses. This model was used to compute two distinct shear stress waveforms, one for the ventricular surface and one for the aortic surface. These waveforms were then applied experimentally to cultured human endothelial cells and the expression of several pathophysiological relevant genes was assessed. Compared to endothelial cells subjected to shear stress waveforms representative of the aortic face, the endothelial cells subjected to the ventricular waveform showed significantly increased expression of the “atheroprotective” transcription factor Kruppel-like factor 2 (KLF2) and the matricellular protein Nephroblastoma overexpressed (NOV), and suppressed expression of chemokine Monocyte-chemotactic protein-1 (MCP-1). Our observations suggest that the difference in shear stress waveforms between the two sides of the aortic valve leaflet may contribute to the documented differential side-specific gene expression, and may be relevant for the development and progression of CAS and the potential role of endothelial mechanotransduction in this disease.National Institutes of Health (U.S.) (Molecular, Cellular, and Tissue Biomechanics training grant (T32 EB006348))National Institutes of Health (U.S.) (NHLBI RO1-HL7066686)Charles Stark Draper Laboratory (Fellowship

Targeting RNS/caveolin-1/MMP signaling cascades to protect against cerebral ischemia-reperfusion injuries: potential application for drug discovery

Reactive nitrogen species (RNS) play important roles in mediating cerebral ischemia-reperfusion injury. RNS activate multiple signaling pathways and participate in different cellular events in cerebral ischemia-reperfusion injury. Recent studies have indicated that caveolin-1 and matrix metalloproteinase (MMP) are important signaling molecules in the pathological process of ischemic brain injury. During cerebral ischemia-reperfusion, the production of nitric oxide (NO) and peroxynitrite (ONOO-), two representative RNS, down-regulates the expression of caveolin-1 (Cav-1) and, in turn, further activates nitric oxide synthase (NOS) to promote RNS generation. The increased RNS further induce MMP activation and mediate disruption of the blood-brain barrier (BBB), aggravating the brain damage in cerebral ischemia-reperfusion injury. Therefore, the feedback interaction among RNS/Cav-1/MMPs provides an amplified mechanism for aggravating ischemic brain damage during cerebral ischemia-reperfusion injury. Targeting the RNS/Cav-1/MMP pathway could be a promising therapeutic strategy for protecting against cerebral ischemia-reperfusion injury. In this mini-review article, we highlight the important role of the RNS/Cav-1/MMP signaling cascades in ischemic stroke injury and review the current progress of studies seeking therapeutic compounds targeting the RNS/Cav-1/MMP signaling cascades to attenuate cerebral ischemia-reperfusion injury. Several representative natural compounds, including calycosin-7-O-β-D-glucoside, baicalin, Momordica charantia polysaccharide (MCP), chlorogenic acid, lutein and lycopene, have shown potential for targeting the RNS/Cav-1/MMP signaling pathway to protect the brain in ischemic stroke. Therefore, the RNS/Cav-1/MMP pathway is an important therapeutic target in ischemic stroke treatment.published_or_final_versio

PET Imaging in Altered States of Consciousness: Coma, Sleep, and Hypnosis

peer reviewedPositron emission tomography (PET) allows studies of cerebral metabolism and blood flow and has been widely used to investigate physiological mechanisms underlying altered states of consciousness. Consciousness is characterized by two components: wakefulness and awareness. In this chapter, we review the current literature on brain metabolism during pathological loss of consciousness (vegetative/unresponsive or minimally conscious states), sleep (in healthy subjects and in patients with insomnia), and under hypnosis. By identifying brain areas specifically involved in conscious processing, these studies have contributed to our understanding of the underlying physiology of consciousness. The precuneal and cingulate cortices, for example, seem to be key areas for maintaining conscious awareness. FDG-PET further allowed the identification of the minimal energetic requirement for conscious awareness in this population, which corresponds to 42% of normal cortical activity. Up to now, it is the most accurate neuroimaging tool regarding the diagnosis of patients with disorders of consciousness. In the future, its use as part of multimodal assessment could improve diagnosis and prognosis in this challenging population. In sleep, a greater activity of the precuneus/posterior cingulate cortex and the fronto-parietal areas during non rapid eye movement sleep also seems to play a role in disorders such as insomnia. Other areas such as the hypothalamus, amygdala, or temporo-occipital cortex seem to play a role in different states such as rapid eye movement sleep and hypnosis. PET studies permit a better comprehension of the neural correlates of consciousness and to identify the implication of specific neural areas and networks in altered states of consciousness in post-comatose patients, sleep and induced hypnosis