Heme cytotoxicity is the consequence of endoplasmic reticulum stress in atherosclerotic plaque progression.

Hemorrhage and hemolysis with subsequent heme release are implicated in many pathologies. Endothelial cells (ECs) encounter large amount of free heme after hemolysis and are at risk of damage from exogenous heme. Here we show that hemorrhage aggravates endoplasmic reticulum (ER) stress in human carotid artery plaques compared to healthy controls or atheromas without hemorrhage as demonstrated by RNA sequencing and immunohistochemistry. In EC cultures, heme also induces ER stress. In contrast, if cultured ECs are pulsed with heme arginate, cells become resistant to heme-induced ER (HIER) stress that is associated with heme oxygenase-1 (HO-1) and ferritin induction. Knocking down HO-1, HO-2, biliverdin reductase, and ferritin show that HO-1 is the ultimate cytoprotectant in acute HIER stress. Carbon monoxide-releasing molecules (CORMs) but not bilirubin protects cultured ECs from HIER stress via HO-1 induction, at least in part. Knocking down HO-1 aggravates heme-induced cell death that cannot be counterbalanced with any known cell death inhibitors. We conclude that endothelium and perhaps other cell types can be protected from HIER stress by induction of HO-1, and heme-induced cell death occurs via HIER stress that is potentially involved in the pathogenesis of diverse pathologies with hemolysis and hemorrhage including atherosclerosis.

Case report of an unusual presentation of Staphylococcus aureus induced toxic shock syndrome/hyperimmunoglobulinemia E syndrome.

RATIONALE: Toxic shock syndrome (TSS) typically is an acute onset multi-organ infection caused by TSS toxin-1 producing Staphylococcus aureus. Herein we describe a highly unusual case report. PATIENT CONCERNS: A male patient self-referred to the University of Minnesota Hospital with a chronic history of S aureus infection with accompanying fever, hypotension, and nonhealing, football-sized lesion on his leg. DIAGNOSIS: An unusual case presentation of TSS/hyperimmunoglobulin E syndrome is described. The patient had a leg wound from which TSS toxin-1 S aureus was isolated. The patient exhibited characteristic skewing of T cells to those with variable region, ß-chain T cell receptor-2. Other patients have been seen with related presentations. INTERVENTIONS: The following therapeutic regimen was instituted: vigorous antibacterial scrubs several times daily plus intravenous Ancef 3 days each month; intravenous infusions of immunoglobulin G infusions (28 gm) every 3 weeks; and weekly subcutaneous injections of recombinant granulocyte colony-stimulating factor. OUTCOME: Improvement was obvious within 3 months: no further cellulitic episodes occurred; the patient regained 95 pounds in 9 months; blanching and cyanosis of fingers disappeared within 3 months as did intractable pain although mild hypesthesias continued for 2 years; erythroderma resolved, and repeat skin biopsies performed after 2 years no longer demonstrated T cell receptor skewing. Although IgE levels have not completely returned to normal, the patient remains in excellent health. LESSONS: We propose that staphylococcal TSST-1 was responsible for the serious problems suffered by this patient as suggested by the following features: rapid onset of chronic, life-threatening, disorder that began with an episode of staphylococcal sepsis; the extraordinary elevation of IgE levels in this previously non-atopic individual; the acquired severe granulocyte chemotactic defect that accompanied this hyperimmunoglobulinemia ("Job Syndrome") with its accompanying wound-healing defect; and the striking diffuse erythroderma, including palmar erythema ("Red Man Syndrome") with hypotension and fever that also characterizes TSS.

Complement, oxidants, and endothelial injury: how a bedside observation opened a door to vascular biology.

A single encounter with a dialysis patient led to the study of complement and neutrophil aggregation, which in turn spawned our work and the remarkable development of the field of vascular biology. As our understanding of these cellular interactions and the signaling pathways involved in these processes has expanded, so has our appreciation for the broad impact of this work on an array of human diseases.

Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment.

Iron-derived reactive oxygen species are involved in the pathogenesis of numerous vascular disorders. One abundant source of redox active iron is heme, which is inherently dangerous when it escapes from its physiologic sites. Here, we present a review of the nature of heme-mediated cytotoxicity and of the strategies by which endothelium manages to protect itself from this clear and present danger. Of all sites in the body, the endothelium may be at greatest risk of exposure to heme. Heme greatly potentiates endothelial cell killing mediated by leukocytes and other sources of reactive oxygen. Heme also promotes the conversion of low-density lipoprotein to cytotoxic oxidized products. Hemoglobin in plasma, when oxidized, transfers heme to endothelium and lipoprotein, thereby enhancing susceptibility to oxidant-mediated injury. As a defense against such stress, endothelial cells upregulate heme oxygenase-1 and ferritin. Heme oxygenase opens the porphyrin ring, producing biliverdin, carbon monoxide, and a most dangerous product-redox active iron. The latter can be effectively controlled by ferritin via sequestration and ferroxidase activity. These homeostatic adjustments have been shown to be effective in the protection of endothelium against the damaging effects of heme and oxidants; lack of adaptation in an iron-rich environment led to extensive endothelial damage in humans.