Objective-Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results-We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (PϽ0.0001) in coronary arteries. Conclusion-We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients.HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. Key Words: aging Ⅲ atherosclerosis Ⅲ pathology Ⅲ peripheral arterial disease Ⅲ progeria H utchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, fatal, progressive premature aging syndrome. Symptoms usually begin with failure to thrive or sclerodermatous skin changes, heralding generalized loss of subcutaneous fat, alopecia, osteopenia and acroosteolysis, and joint contracture. Death occurs at a mean age of 13 years because of myocardial infarction or stroke. 1 The majority of HGPS cases are caused by a single de novo nucleotide substitution at position 1824 (C3 T) in the LMNA gene. 2,3 The normal LMNA protein product, lamin A, is a key component of the inner nuclear lamina, which functions in nuclear structure, chromatin organization, and gene transcription. 4 The silent mutation in HGPS leads to alternative splicing at the 3Ј end of the LMNA mRNA and a 150-nucleotide deletion from the prelamin A transcript resulting in a mutant lamin A protein called progerin, which lacks 50 amino acids near its C-terminal end. 5 In non-HGPS individuals, there is convincing evidence that the HGPS splice site is functional and can lead to progerin accumulation over time, although to a lesser degree than in children with HGPS. 6 In HGPS, the cryptic donor splice site shares 6 of 7 bases with the consensus splice sequence, while non-HGPS individuals share 5 of 7 bases with the consensus splice sequence. Thus, non-HGPS individuals utilize the splice site less often. Progerin is not apparent in early passage non-HGPS cultured fibroblasts and skin biopsies, but it accumulates with increasing cell passage and donor age. 7,8 Thus, progerin is likely a previous...
The perilipins are the most abundant proteins at the surfaces of lipid droplets in adipocytes and are also found in steroidogenic cells. To investigate perilipin function, perilipin A, the predominant isoform, was ectopically expressed in fibroblastic 3T3-L1 pre-adipocytes that normally lack the perilipins. In control cells, fluorescent staining of neutral lipids with Bodipy 493/ 503 showed a few minute and widely dispersed lipid droplets, while in cells stably expressing perilipin A, the lipid droplets were more numerous and tightly clustered in one or two regions of the cytoplasm. Immunofluorescence microscopy revealed that the ectopic perilipin A localized to the surfaces of the tiny clustered lipid droplets; subcellular fractionation of the cells using sucrose gradients confirmed that the perilipin A localized exclusively to lipid droplets. Cells expressing perilipin A stored 6 -30-fold more triacylglycerol than control cells due to reduced lipolysis of triacylglycerol stores. The lipolysis of stored triacylglycerol was 5 times slower in lipid-loaded cells expressing perilipin A than in lipid-loaded control cells, when triacylglycerol synthesis was blocked with 6 M triacsin C. This stabilization of triacylglycerol was not due to the suppression of triacylglycerol lipase activity by the expression of perilipin A. We conclude that perilipin A increases the triacylglycerol content of cells by forming a barrier that reduces the access of soluble lipases to stored lipids, thus inhibiting triacylglycerol hydrolysis. These studies suggest that perilipin A plays a major role in the regulation of triacylglycerol storage and lipolysis in adipocytes.Lipid droplets in adipocytes store the body's major energy reserves as triacylglycerols. These structures contain a large core of neutral lipid, primarily triacylglycerol, covered by a phospholipid monolayer. The intracellular mechanisms that control the storage and release of triacylglycerols are largely uncharacterized, yet are likely to be fundamental to understanding the regulation of energy metabolism in the body. Recent studies have shown that lipid droplets are covered with a proteinaceous coat; the functions and identities of the component proteins have not been fully elucidated. The first identified lipid droplet-specific proteins are the perilipins (1-7), a family of proteins coating the surfaces of lipid droplets of adipocytes and steroidogenic cells of adrenal cortex, testes, and ovaries, but lacking in other types of cells and in other cellular compartments. The perilipins are encoded by a single copy gene that gives rise to multiple mRNAs by alternative splicing mechanisms 1 ; these mRNAs are translated to yield the three described protein isoforms (2, 4). Perilipin A is the predominant isoform in both adipocytes and steroidogenic cells, perilipin B is found primarily in adipocytes, and perilipin C is unique to steroidogenic cells. Perilipin A is the most abundant protein on highly purified lipid droplets isolated from fully differentiated cultured 3T3-L1 adip...
Children with Hutchinson-Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and͞or stroke usually in their second decade of life. For the vast majority of cases, a de novo point mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed ''progerin,'' which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.lamin A ͉ atherosclerosis ͉ laminopathy
Adipose tissue IL-6 expression is increased in obesity and is a strong predictor of abnormalities in adipocyte and systemic metabolism. We used adipose tissue organ culture to test the direct effects of IL-6 on leptin expression, lipolysis, and lipoprotein lipase activity. To assess possible interactions with the hormonal milieu, IL-6 effects were tested in the presence or absence of insulin and/or glucocorticoid [dexamethasone (dex)]. Because omental (Om) and abdominal sc depots differ in IL-6 expression, their responses to exogenous IL-6 were compared. Although IL-6 had no significant effects under basal conditions, culture with the combination of IL-6 and dex, compared with dex alone, for 2 d increased leptin in both depots [+95 +/- 30% (sc) and +67 +/- 19% (Om), P < 0.01]; IL-6 did not affect leptin production when added in the presence of insulin. Culture with IL-6 in the absence of hormones moderately increased lipolysis during culture in both sc and Om [+79 +/- 23% (sc) and +26 +/- 9% (Om), each P < 0.01]. IL-6 markedly reduced the high levels of lipoprotein lipase activity in tissue cultured with insulin plus dex. We conclude that high local concentrations of IL-6 can modulate leptin production and lipid metabolism in human adipose tissue.
Frontiers in Immunology | www.frontiersin.org absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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