Age-associated central arterial wall stiffness is linked to extracellular matrix remodeling, including fibrosis and vascular calcification. Angiotensin II induces both matrix metalloproteinase 2 ...(MMP2) and calpain-1 expression and activity in the arterial wall. However, the role of calpain-1 in MMP2 activation and extracellular matrix remodeling remains unknown. Dual histo-immunolabeling demonstrates colocalization of calpain-1 and MMP2 within old rat vascular smooth muscle cells. Overexpression of calpain-1 induces MMP2 transcripts, protein levels, and activity, in part, by increasing the ratio of membrane type 1 MMPs to tissue inhibitor of metalloproteinases 2. These effects of calpain-1 overexpression-induced MMP2 activation are linked to increased collagen I and III production and vascular calcification. In addition, overexpression of calpain-1 also induces transforming growth factor-β1/Smad signaling, elastin degradation, alkaline phosphatase activation, and total calcium content but reduces the expression of calcification inhibitors, osteopontin, and osteonectin, in cultured vascular smooth muscle cells in vitro and in carotid artery rings ex vivo. Furthermore, both calpain-1 and collagen II increase with aging within human aortic intima. Interestingly, in aged human aortic wall, both calpain-1 and collagen II are highly expressed in artherosclerotic plaque areas compared with grossly normal areas. Cross-talk of 2 proteases, calpain-1 and MMP2, leads to secretion of active MMP2, which modulates extracellular matrix remodeling via enhancing collagen production and facilitating vascular calcification. These results establish calpain-1 as a novel molecular candidate to retard age-associated extracellular matrix remodeling and its attendant risk for hypertension and atherosclerosis.
Age-associated structural and functional remodeling of the arterial wall produces a productive environment for the initiation and progression of hypertension and atherosclerosis. Chronic aging stress ...induces low-grade proinflammatory signaling and causes cellular proinflammation in arterial walls, which triggers the structural phenotypic shifts characterized by endothelial dysfunction, diffuse intimal-medial thickening, and arterial stiffening. Microscopically, aged arteries exhibit an increase in arterial cell senescence, proliferation, invasion, matrix deposition, elastin fragmentation, calcification, and amyloidosis. These characteristic cellular and matrix alterations not only develop with aging but can also be induced in young animals under experimental proinflammatory stimulation. Interestingly, these changes can also be attenuated in old animals by reducing low-grade inflammatory signaling. Thus, mitigating age-associated proinflammation and arterial phenotype shifts is a potential approach to retard arterial aging and prevent the epidemic of hypertension and atherosclerosis in the elderly.
In the quest for direct dark matter detection, innovative approaches to lower the detection threshold and explore the sub-GeV mass range, have gained high relevance in the last decade. This study ...presents the pioneering use of Gallium Arsenide (GaAs) as a low-temperature calorimeter for probing dark matter-electron interactions within the DAREDEVIL (DARk-mattEr DEVIces for Low energy detection) project. Our experimental setup features a GaAs crystal at an ultralow temperature of 15 mK, coupled with a Neutron Transmutation Doped Germanium (NTD-Ge) thermal sensor for precise energy estimation. This configuration is the first step towards detecting single electrons scattered by dark matter particles within the GaAs crystal, to improve the sensitivity to low-mass dark matter candidates significantly. Taking advantage of the production of optical phonons in polar materials such as GaAs gives the possibility to study the scattering of sub-MeV dark matter. This paper presents a detailed analysis of the detector’s response, using a calibration spectrum using
α
particles and X-ray events. While the results do not meet the ambitious eV scale threshold yet, they establish a solid benchmark for assessing the detector’s current performance and sensitivity. This work not only highlights the detector’s potential but also sets the stage for future enhancements aimed at achieving the eV threshold, underscoring the promising direction of this detector technology. These findings demonstrate the feasibility of using GaAs as a cryogenic calorimeter and hence open new avenues for investigating the elusive nature of dark matter through innovative direct detection techniques.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells ...(VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.
The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001.
Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medin, a small 50-amino acid peptide, is an internal cleaved product from the second discoidin domain of milk fat globule epidermal growth factor VIII (MFG-E8) protein. Medin has been reported as the ...most common amylogenic protein in the upper part of the arterial system, including aortic, temporal, and cerebral arterial walls in the elderly. Medin has a high affinity to elastic fibers and is closely associated with arterial degenerative inflammation, elastic fiber fragmentation, calcification, and amyloidosis. In vitro, treating with the medin peptide promotes the inflammatory phenotypic shift of both endothelial cells and vascular smooth muscle cells. In vitro, ex vivo, and in vivo studies demonstrate that medin enhances the abundance of reactive oxygen species and reactive nitrogen species produced by both endothelial cells and vascular smooth muscle cells and promotes vascular endothelial dysfunction and arterial stiffening. Immunostaining and immunoblotting analyses of human samples indicate that the levels of medin are increased in the pathogenesis of aortic aneurysm/dissection, temporal arteritis, and cerebrovascular dementia. Thus, medin peptide could be targeted as a biomarker diagnostic tool or as a potential molecular approach to curbing the arterial degenerative inflammatory remodeling that accompanies aging and disease.
Transition-edge sensors (TES) are outstanding calorimeters based on the steep superconductive transition of a metallic film. Among other photon detectors, they are renowned for the fine energy ...resolution, the photon-number resolving (PNR) capability and an extremely low dark count rate. Due to the broad detection spectrum, from gamma-ray to visible and submillimetre wavelengths, TESs are highly sought-after in a great variety of fields, such as X-ray detection and quantum technologies. Each of these fields demands a step forward in TESs performance with regards to the recovery time and energy resolution. Here we present a program, primarily capable of predicting the performance of TESs. Using established theoretical and empirical methods we developed a software that allows the users to choose active area, thickness, and material composition of a TES and to calculate its performance. Furthermore, the software can simulate TES properties at different working points. The aim of the software is to minimize the production cost and speed up the overall process for the creation of new devices with improved performance.
Aging is a major risk factor for quintessential cardiovascular diseases, which are closely related to arterial proinflammation. The age‐related alterations of the amount, distribution, and properties ...of the collagen fibers, such as cross‐links and degradation in the arterial wall, are the major sequelae of proinflammation. In the aging arterial wall, collagen types I, II, and III are predominant, and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule‐EGF‐VIII, and transforming growth factor‐beta 1 (TGF‐β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP‐2) and activates profibrogenic TGF‐β1 signaling, contributing to profibrosis. The age‐associated increase in activated MMP‐2 cleaves latent TGF‐β and subsequently increases TGF‐β1 activity leading to collagen deposition in the arterial wall. Furthermore, a blockade of the proinflammatory signaling pathway alleviates the fibrogenic signaling, reduces profibrosis, and prevents arterial stiffening with aging. Thus, age‐associated proinflammatory‐profibrosis coupling is the underlying molecular mechanism of arterial stiffening with advancing age.
Summary
An accumulation of milk fat globule EGF‐8 protein (MFG‐E8) occurs within the context of arterial wall inflammatory remodeling during aging, hypertension, diabetes mellitus, or ...atherosclerosis. MFG‐E8 induces VSMC invasion, but whether it affects VSMC proliferation, a salient feature of arterial inflammation, is unknown. Here, we show that in the rat arterial wall in vivo, PCNA and Ki67, markers of cell cycle activation, increase with age between 8 and 30 months. In fresh and early passage VSMC isolated from old aortae, an increase in CDK4 and PCNA, an increase in the acceleration of cell cycle S and G2 phases, decrease in the G1/G0 phase, and an increase in PDGF and its receptors confer elevated proliferative capacity, compared to young VSMC. Increased coexpression and physical interaction of MFG‐E8 and integrin αvβ5 occur with aging in both the rat aortic wall in vivo and in VSMC in vitro. In young VSMC in vitro, MFG‐E8 added exogenously, or overexpressed endogenously, triggers phosphorylation of ERK1/2, augmented levels of PCNA and CDK4, increased BrdU incorporation, and promotes proliferation, via αvβ5 integrins. MFG‐E8 silencing, or its receptor inhibition, or the blockade of ERK1/2 phosphorylation in these cells reduces PCNA and CDK4 levels and decelerates the cell cycle S phase, conferring a reduction in proliferative capacity. Collectively, these results indicate that MFG‐E8 in a dose‐dependent manner coordinates the expression of cell cycle molecules and facilitates VSMC proliferation via integrin/ERK1/2 signaling. Thus, an increase in MFG‐E8 signaling is a mechanism of the age‐associated increase in aortic VSMC proliferation.
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