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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 (P<0.0001) in coronary arteries., Conclusions: 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.

Rationale: Arginine methylation by protein N-arginine methyltransferases (PRMTs) is an important posttranslational modification in the regulation of protein signaling. PRMT2 contains a highly conserved catalytic Ado-Met binding domain, but the enzymatic function of PRMT2 with respect to methylation is unknown. The JAK-STAT pathway is proposed to be regulated through direct arginine methylation of STAT transcription factors, and STAT3 signaling is known to be required for leptin regulation of energy balance., Objective: To identify the potential role of STAT3 arginine methylation by PRMT2 in the regulation of leptin signaling and energy homeostasis., Methods and Results: We identified that PRMT2(-/-) mice are hypophagic, lean, and have significantly reduced serum leptin levels. This lean phenotype is accompanied by resistance to food-dependent obesity and an increased sensitivity to exogenous leptin administration. PRMT2 colocalizes with STAT3 in hypothalamic nuclei, where it binds and methylates STAT3 through its Ado-Met binding domain. In vitro studies further clarified that the Ado-Met binding domain of PRMT2 induces STAT3 methylation at the Arg31 residue. Absence of PRMT2 results in decreased methylation and prolonged tyrosine phosphorylation of hypothalamic STAT3, which was associated with increased expression of hypothalamic proopiomelanocortin following leptin stimulation., Conclusions: These data elucidate a molecular pathway that directly links arginine methylation of STAT3 by PRMT2 to the regulation of leptin signaling, suggesting a potential role for PRMT2 antagonism in the treatment of obesity and obesity-related syndromes.

The breakdown of myofibrillar and sarcoplasmic (nonmyofibrillar) proteins are regulated independently in sepsis, however, the factors regulating their synthesis are unknown. In this study, we assessed the effects of sepsis and interleukin-1 receptor antagonist on sarcoplasmic and myofibrillar protein synthesis in gastrocnemius. The rate of sarcoplasmic protein synthesis was 3.5 times that of myofibrillar proteins in control and septic rats. The synthesis of both sarcoplasmic and myofibrillar proteins was diminished proportionately during sepsis (p < .05). Infusion of interleukin-1 receptor antagonist (2 mg.kg.-1.h.-1) prevented the sepsis-induced inhibition of total, sarcoplasmic, and myofibrillar protein synthesis. Changes in the abundance of messenger RNA could not account for the inhibition of protein synthesis observed in sepsis. Furthermore, in vitro translation of messenger RNA isolated from control and septic muscle revealed no major differences. These results suggest the following: 1) the inhibition of total mixed proteins during sepsis is a consequence of reduced synthesis of both myofibrillar and sarcoplasmic proteins; 2) IL-1ra maintains control values of protein synthesis by sparing the reduction in synthesis of both myofibrillar and sarcoplasmic proteins during sepsis; and 3) the abundance of messenger RNA is not a rate-limiting determinant of protein synthesis in muscle from septic rats. An alteration in the translational efficiency of existing mRNA appears to be the major mechanism responsible for the inhibition of protein synthesis during sepsis.