No abstract

We used gene knockout mice to explore the role of Angiopoietinlike-4 (Angptl4) in lipid metabolism as well as to generate antiAngptl4 mAbs with pharmacological activity. Angptl4 ؊/؊ mice had lower triglyceride (TG) levels resulting both from increased very low-density lipoprotein (VLDL) clearance and decreased VLDL production and had modestly lower cholesterol levels. Also, both Angptl4 ؊/؊ suckling mice and adult mice fed a high-fat diet showed reduced viability associated with lipogranulomatous lesions of the intestines and their draining lymphatics and mesenteric lymph nodes. Treating C57BL/6J, ApoE ؊/؊, LDLr ؊/؊, and db/db mice with the anti-Angptl4 mAb 14D12 recapitulated the lipid and histopathologic phenotypes noted in Angptl4 ؊/؊ mice. This demonstrates that the knockout phenotype reflects not only the physiologic function of the Angptl4 gene but also predicts the pharmacologic consequences of Angptl4 protein inhibition with a neutralizing antibody in relevant models of human disease. monoclonal antibody ͉ mouse ͉ triglycerides ͉ cholesterol

No abstract

No abstract

Concomitant cardiac amyloidosis (CA) in severe aortic stenosis (AS) is difficult to recognize, since both conditions are associated with concentric left ventricular thickening. We aimed to assess type, frequency, screening parameters, and prognostic implications of CA in AS.

apeutic intervention for diseases such as atherosclerosis, pancreatitis, or dyslipidemia associated with metabolic syndrome or type II diabetes ( 1-3 ). Central to triglyceride metabolism is lipoprotein lipase (LPL), an extracellular enzyme primarily located in the vascular beds of many tissues ( 3,4 ). LPL catalyzes the hydrolysis of the triglyceride component of chylomicrons (CM) and VLDL, which constitute the major forms of triglycerides in plasma ( 3, 5 ). Although LPL is expressed in many different tissues, the enzyme is expressed at high levels in metabolically active tissues, such as adipose, cardiac muscle, and skeletal muscle, where fatty acids released by the action of LPL are stored or used ( 4 ).LPL appears to be regulated by a variety of mechanisms. Several apolipoproteins associated with CM and VLDL, including apolipoprotein CII (APOC2) and apolipoprotein AV (APOA5), stimulate LPL activity ( 6-9 ) apparently by increasing its V max ( 10,11 ). In contrast, apolipoproteins CI (APOC1) and CIII (APOC3) can inhibit LPL activity ( 7,12 ). LPL is inherently unstable and proteins or other factors that either stabilize or destabilize LPL are likely to play a role in regulating its in vivo activity ( 13 ). The active form of LPL exists as a head-totail homodimer, which dissociates into metastable monomers. These monomers can reassociate to form catalytically active LPL or they can undergo conformational changes, forming inactive, stable monomers. The spontaneous in- Our understanding of how triglyceride (TG) metabolism is regulated is essential for designing avenues of ther-

Angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4) are secreted proteins that regulate triglyceride (TG) metabolism in part by inhibiting lipoprotein lipase (LPL).Recently, we showed that treatment of wild-type mice with monoclonal antibody (mAb) 14D12, specific for ANGPTL4, recapitulated the Angptl4 knock-out (؊/؊) mouse phenotype of reduced serum TG levels. In the present study, we mapped the region of mouse ANGPTL4 recognized by mAb 14D12 to amino acids Gln 29 -His 53 , which we designate as specific epitope 1 (SE1). The 14D12 mAb prevented binding of ANGPTL4 with LPL, consistent with its ability to neutralize the LPL-inhibitory activity of ANGPTL4. Alignment of all angiopoietin family members revealed that a sequence similar to ANGPTL4 SE1 was present only in ANGPTL3, corresponding to amino acids Glu 32 -His 55 . We produced a mouse mAb against this SE1-like region in ANGPTL3. This mAb, designated 5.50.3, inhibited the binding of ANGPTL3 to LPL and neutralized ANGPTL3-mediated inhibition of LPL activity in vitro. Treatment of wild-type as well as hyperlipidemic mice with mAb 5.50.3 resulted in reduced serum TG levels, recapitulating the lipid phenotype found in Angptl3 ؊/؊ mice. These results show that the SE1 region of ANGPTL3 and ANGPTL4 functions as a domain important for binding LPL and inhibiting its activity in vitro and in vivo. Moreover, these results demonstrate that therapeutic antibodies that neutralize ANGPTL4 and ANGPTL3 may be useful for treatment of some forms of hyperlipidemia.Lipoprotein lipase (LPL) 5 plays a pivotal role in lipid metabolism by catalyzing the hydrolysis of plasma triglycerides (TGs).LPL is likely to be regulated by mechanisms that depend on nutritional status and on the tissue in which it is expressed (1-3). Two secreted proteins, angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4), play important roles in the regulation of LPL activity (4, 5). ANGPTL3 and ANGPTL4 consist of a signal peptide, an N-terminal segment containing coiled-coil domains, and a C-terminal fibrinogen-like domain. The N-terminal segment as well as full-length ANGPTL3 and ANGPTL4 have been shown to inhibit LPL activity, and deletion of the N-terminal segment of ANGPTL3 and ANGPTL4 resulted in total loss of LPL-inhibiting activity (6, 7). These observations clearly indicate that the N-terminal region of ANGPTL4 contains the functional domain that inhibits LPL and affects plasma lipid levels. The coiled-coil domains have been proposed to be responsible for oligomerization (8); however, it is not known whether the coiled-coil domains directly mediate the inhibition of LPL activity.To define the physiological role of ANGPTL4 more clearly, we characterized the pharmacological consequences of ANGPTL4 inhibition in mice treated with the ANGPTL4-neutralizing monoclonal antibody (mAb) 14D12 (9). Injection of mAb 14D12 significantly lowered fasting TG levels in C57BL/6J mice relative to levels in C57BL/6J mice treated with an isotypematched anti-KLH control (KLH) mAb (9). These reduced TG...

The cerebrovascular system continuously delivers oxygen and energy substrates to the brain, which is one of the organs with the highest basal energy requirement in mammals. Discontinuities in the delivery lead to fatal consequences for the brain tissue. A detailed understanding of the structure of the cerebrovascular system is important for a multitude of (patho-)physiological cerebral processes and many noninvasive functional imaging methods rely on a signal that originates from the vasculature. Furthermore, neurodegenerative diseases often involve the cerebrovascular system and could contribute to neuronal loss. In this review, we focus on the cortical vascular system. In the first part, we present the current knowledge of the vascular anatomy. This is followed by a theory of topology and its application to vascular biology. We then discuss possible interactions between cerebral blood flow and vascular topology, before summarizing the existing body of the literature on quantitative cerebrovascular topology.