Large epidemiologic analyses of cardiovascular injuries have been limited to studies of military campaigns compiled from many surgeons working in many hospitals with variable protocols. A detailed civilian vascular trauma registry provides a unique opportunity for an epidemiologic evolutionary profile. During the last 30 years in a single civilian trauma center directed by a consistent evaluation and treatment philosophy, 4459 patients were treated for 5760 cardiovascular injuries. Eighty-six per cent of the patients were male, and the average age was 30.0 years. Penetrating trauma was the etiology in more than 90% (GSW,51.5%; SW,31.1%; SGW,6.8%). All other injuries were iatrogenic or secondary to blunt trauma. Truncal injuries (including the neck) accounted for 66% of all injuries treated, while lower extremity injuries (including the groin) accounted for only 19%. Injuries to the abdominal vasculature accounted for 33.7% of the injuries. One thousand fifty-seven patients had 2 or more concurrent vascular injuries, and 32 patients had 4 or more separate vascular injuries. The 27 patients-per-year average of the early 1960s has risen to a current average of 213 patients per year. Economic and population factors influenced wounding agents and injury patterns during the evaluation period. This extensive civilian series presents epidemiologic profiles that are distinctly different from military reports and serves as a guide for current trauma center and health planners.

The small heat shock-related protein 20 (HSP20) is present in four isoforms in bovine carotid artery smooth muscles. Three of the isoforms are phosphorylated and one is not. Increases in the phosphorylation of two isoforms of HSP20 (isoform 3, pI 5.9; and 8, pI 5.7) are associated with cyclic nucleotide-dependent relaxation of bovine carotid artery smooth muscles. Increases in the phosphorylation of another isoform (isoform 4, pI 6.0) are associated with phorbol ester-induced contraction of bovine carotid artery smooth muscles. In this investigation we determined that isoforms 3 and 8 are phosphorylated on Ser 16 of the HSP20 molecule during activation of cAMP-dependent signaling pathways. Phosphorylation state-specific antibodies produced against a peptide containing phosphorylated Ser 16 recognized isoforms 3 and 8 but not isoform 4. In human vascular tissue, only isoform 3 is present. Incubation of transiently permeabilized strips of bovine carotid artery smooth muscle with synthetic peptides in which Ser 16 is phosphorylated, inhibits contractile responses to high extracellular KCl and to serotonin. These data suggest that phosphorylation of HSP20 on Ser 16 modulates cAMP-dependent vasorelaxation.A major phosphorylation event that occurs with cyclic nucleotide-dependent relaxation of vascular smooth muscle is an increase in the phosphorylation of two 20-kDa proteins (isoform 3, pI 5.9; and 8, pI 5.7) (1-3). We recently identified these 20-kDa phosphoproteins as different phosphorylated forms of a small heat shock-related protein, HSP20 1 (4). In addition, HSP20 can be phosphorylated in vitro by both cAMP-dependent protein kinase (PKA) and cGMP-dependent protein kinase (PKG) (4). HSP20 is also phosphorylated during endothelialdependent vasorelaxation of isolated segments of bovine carotid artery smooth muscle (5).In a vascular smooth muscle, umbilical artery smooth muscle, that is refractory to cyclic nucleotide-dependent vasorelaxation, there is no significant increase in the phosphorylation of HSP20 in response to activation of PKA or PKG (2). HSP20 is present in umbilical artery smooth muscle and can be phosphorylated by PKA in vitro using homogenates of umbilical smooth muscle (6). Taken together, these data support a role for phosphorylated HSP20 in mediating cyclic nucleotide-dependent vasorelaxation.Histamine and phorbol ester-induced contractions of bovine carotid artery smooth muscle are associated with an increase in the phosphorylation of another 20-kDa protein (isoform 4, pI 6.0) (1). The subsequent activation of cyclic nucleotide-dependent signaling pathways leads to a decrease in the phosphorylation of isoform 4. This 20-kDa protein is immunoreactive with specific polyclonal antibodies raised against HSP20 (4). Thus, increases in the phosphorylation of this isoform of HSP20 are associated with smooth muscle contraction and decreases are associated with activation of cyclic nucleotide-dependent signaling pathways.The purpose of this investigation was to determine the specific site on the HSP20 mo...

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Activation of cyclic nucleotide-dependent signaling pathways leads to the relaxation of various smooth muscles. One of the major phosphorylation events associated with cyclic nucleotide-dependent vasorelaxation in bovine trachealis and carotid artery smooth muscle is the phosphorylation of two 20-kDa phosphoproteins with pI values of 5.7 and 5.9 (previously designated pp8 and pp3, respectively). The present studies sought to determine the identities of pp3 and pp8 in vascular smooth muscle. The phosphopeptide maps for the pp8 and pp3 proteins were similar. Preparative two-dimensional gel electrophoresis and amino acid sequencing of a peptide fragment of the pp3 protein revealed a sequence identical to a 20-kDa heat shock-related protein (HSP20) previously purified from skeletal muscle. Western blot and immunoprecipitation analysis with anti-HSP20 antibodies demonstrated that the pp3 and pp8 proteins are phosphorylated forms of HSP20. In addition, HSP20 could be phosphorylated in vitro by both cAMP-dependent protein kinase and cGMP-dependent protein kinase. These data suggest that the phosphorylation of the heat shock-related protein HSP20 is associated with cyclic nucleotide-dependent relaxation of vascular smooth muscle.Activation of cyclic nucleotide-dependent signaling pathways leads to the relaxation of vascular smooth muscle. Isoproterenol, prostacyclin, and forskolin stimulate the adenylate cyclase/ cAMP pathway and activate cAMP-dependent protein kinase (PKA) 1 (1). Nitric oxide, atrial natriuretic peptide, sodium nitroprusside, and nitroglycerin stimulate the guanylate cyclase/ cGMP pathway and activate cGMP-dependent protein kinase (PKG) (2).A number of investigators have sought to identify the protein targets for PKA and PKG that are involved in smooth muscle relaxation. Two sites of particular interest have emerged. First, the phosphorylation of myosin light chain kinase by PKA decreases its sensitivity to activation by Ca 2ϩ -calmodulin, leading to a decrease in the phosphorylation of the myosin light chains (3). Second, PKA and/or PKG activation leads to changes in the activities of one or more Ca 2ϩ channels and/or Ca 2ϩ pumps, thereby reducing the intracellular Ca 2ϩ concentrations (4, 5). However, there is no simple correlation between the extent of myosin light chain phosphorylation and the state of contraction of vascular smooth muscle (6, 7). On the other hand, cyclic nucleotide-dependent relaxation of intact muscle strips can occur under conditions where the Ca 2ϩ concentration is fixed at either a low or a high concentration (8 -12).The relaxation of several different types of smooth muscles by forskolin or sodium nitroprusside is associated with an increase in the extent of phosphorylation of two 20-kDa proteins with pI values of 5.9 and 5.7, previously described as proteins 3 (pp3) and 8 (pp8), respectively (13,14). In addition, the extent of phosphorylation of these two proteins increases during forskolin or sodium nitroprusside-induced vasorelaxation under circumstances where the intrace...

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Activated macrophages (M phi s) are important participants in host defense, but their uncontrolled activation leads rapidly to septic shock and death. One mechanism for regulating other dangerous cells in the immune system is programmed cell death, or apoptosis. Monocytes are known to undergo spontaneous apoptosis upon leaving the circulation unless provided with specific survival signals, but mature tissue M phi s are more robust cells, and it was not clear that they could be similarly regulated by apoptosis. We now show that during differentiation monocytes rapidly lose their sensitivity to apoptosis triggered by passive cytokine withdrawal, but they may retain a novel pathway which initiates apoptosis after activation with specific stimuli (zymosan and phorbol esters). Sensitivity to activation-induced apoptosis was developmentally determined, being downregulated by the maturation-promoting cytokine macrophage colony-stimulating factor but stably upregulated by even transient exposure to the proinflammatory cytokine interferon gamma (IFN-gamma). Apoptosis began within 2-4 h of activation, occurred in > 95% of susceptible cells, and in mixed cocultures selectively affected only those M phi s with a history of IFN-gamma priming. Consistent with a possible role for protein kinase C in the signaling pathway leading to cell death, the kinase inhibitor staurosporine was protective against both phorbol ester- and zymosan-induced apoptosis. Our studies describe a novel form of activation-induced M phi apoptosis which is developmentally regulated by two physiologically relevant cytokines. We speculate that apoptosis may serve to restrict the destructive potential of inflammatory M phi s.

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