Macrophages specialize in removing lipids and debris present in the atherosclerotic plaque. However, plaque progression renders macrophages unable to degrade exogenous atherogenic material and endogenous cargo including dysfunctional proteins and organelles. Here we show that a decline in the autophagy–lysosome system contributes to this as evidenced by a derangement in key autophagy markers in both mouse and human atherosclerotic plaques. By augmenting macrophage TFEB, the master transcriptional regulator of autophagy–lysosomal biogenesis, we can reverse the autophagy dysfunction of plaques, enhance aggrephagy of p62-enriched protein aggregates and blunt macrophage apoptosis and pro-inflammatory IL-1β levels, leading to reduced atherosclerosis. In order to harness this degradative response therapeutically, we also describe a natural sugar called trehalose as an inducer of macrophage autophagy–lysosomal biogenesis and show trehalose's ability to recapitulate the atheroprotective properties of macrophage TFEB overexpression. Our data support this practical method of enhancing the degradative capacity of macrophages as a therapy for atherosclerotic vascular disease.

Nonhealing diabetic wounds are common complications for diabetic patients. Because chronic hypoxia prominently delays wound healing, sustained oxygenation to alleviate hypoxia is hypothesized to promote diabetic wound healing. However, sustained oxygenation cannot be achieved by current clinical approaches, including hyperbaric oxygen therapy. Here, we present a sustained oxygenation system consisting of oxygen-release microspheres and a reactive oxygen species (ROS)–scavenging hydrogel. The hydrogel captures the naturally elevated ROS in diabetic wounds, which may be further elevated by the oxygen released from the administered microspheres. The sustained release of oxygen augmented the survival and migration of keratinocytes and dermal fibroblasts, promoted angiogenic growth factor expression and angiogenesis in diabetic wounds, and decreased the proinflammatory cytokine expression. These effects significantly increased the wound closure rate. Our findings demonstrate that sustained oxygenation alone, without using drugs, can heal diabetic wounds.

Our results show a U-shaped relationship between HDL cholesterol and risk of all-cause mortality across all eGFR categories. The risk is modified by eGFR and cardiovascular disease.

Abstract-Pathological angiogenesis contributes to various ocular, malignant, and inflammatory disorders, emphasizing the need to understand this process on a molecular level. CIB1 (calcium-and integrin-binding protein), a 22-kDa EF-hand-containing protein, modulates the activity of p21-activated kinase 1 in fibroblasts. Because p21-activated kinase 1 also contributes to endothelial cell function, we hypothesized that CIB1 may have a role in angiogenesis. We found that endothelial cells depleted of CIB1 by either short hairpin RNA or homologous recombination have reduced migration, proliferation, and tubule formation. Moreover, loss of CIB1 in these cells decreases p21-activated kinase 1 activation, downstream extracellular signal-regulated kinase 1/2 activation, and matrix metalloproteinase 2 expression, all of which are known to contribute to angiogenesis. Consistent with these findings, tissues derived from CIB1-deficient (CIB1 Ϫ/Ϫ ) mice have reduced growth factor-induced microvessel sprouting in ex vivo organ cultures and in vivo Matrigel plugs. Furthermore, in response to ischemia, CIB1Ϫ/Ϫ mice demonstrate decreased pathological retinal and adaptive hindlimb angiogenesis. Ischemic CIB1 Ϫ/Ϫ hindlimbs also demonstrate increased tissue damage and significantly reduced p21-activated kinase 1 activation. These data therefore reveal a critical role for CIB1 in ischemia-induced pathological and adaptive angiogenesis. I schemia-induced angiogenesis involves both pathological and adaptive angiogenesis and has a clear association with many disorders that involve various types of human tissue. 1 In ischemic retinal diseases, such as diabetic retinopathy, retinopathy of prematurity, and age-related macular degeneration, angiogenesis is excessive; the goal in these retinal diseases is to inhibit ischemia-induced pathological angiogenesis. [2][3][4] Alternatively, in ischemic diseases, such as peripheral vascular disease and ischemic heart disease, the induction of adaptive angiogenesis is beneficial in preventing tissue damage and promoting recovery. 5 Central to this process are vascular endothelial cells (ECs), which respond to both anti-and proangiogenic factors and on activation, undergo a remarkable increase in migration, proliferation, nascent tubule formation, and matrix metalloproteinase (MMP) secretion. 6,7 Identifying exactly which molecules contribute to these processes, but not to physiological angiogenesis (angiogenesis during development and tissue regeneration), will provide better therapeutic targets to alleviate ischemia-associated diseases and aid in our understanding of how pathological angiogenesis arises.CIB1 (also known as calmyrin or kinase-interacting protein [KIP]) is a 22-kDa EF-hand-containing protein identified originally in a yeast 2-hybrid screen as a binding partner for the cytoplasmic tail of the platelet integrin ␣IIb. 8 It was later determined that CIB1 inhibits agonist-induced ␣IIb␤3 activation in megakaryocytes. 9 However, CIB1 is widely distributed, suggesting that it has cellular ...

IMPORTANCE Lower extremity amputation (LEA) is associated with significant morbidity and mortality. However, national temporal trends of LEA incidence rates among US veterans and associated factors have not been well characterized. OBJECTIVE To describe the temporal trends of LEA, characterize associated risk factors, and decompose the associations of these risk factors with changes in temporal trends of LEA among US veterans using Department of Veteran Affairs (VA) services between 2008 and 2018. DESIGN, SETTING, AND PARTICIPANTS This cohort study used VA data from 2008 to 2018 to estimate incidence rates of LEA among veterans using VA services. Cox regression models were used to identify risk factors associated with LEA. Decomposition analyses estimated the associations of changes in prevalence of risk factors with changes in LEA rates. Data were analyzed from October 1, 2007, to September 30, 2018. MAIN OUTCOMES AND MEASURES Toe, transmetatarsal, below-knee, or above-knee LEA. RESULTS A total of 6 493 141 veterans were included (median [interquartile range] age, 64 [54-76] years; 6 060 390 [93.4%] men). Veterans were studied for a median (interquartile range) of 10.9