Circulation Research

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized (“hyperglycemic memory”). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.

In 57 normal subjects (age 20-60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90 degrees upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) beta-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at approximately 0.25 Hz and a low frequency at approximately 0.1 Hz, with a normalized low frequency:high frequency ratio of 3.6 +/- 0.7. With tilt, the low-frequency component became largely predominant (90 +/- 1%) with a low frequency:high frequency ratio of 21 +/- 4. Acute beta-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency:high frequency ratio induced by tilt. Chronic beta-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency:high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency:high frequency ratio (0.7 +/- 0.1); during tilt, the increase in the low frequency:high frequency ratio (8.3 +/- 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency:high frequency ratio at rest of 2.8 +/- 0.7, which became 17 +/- 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Some statistical techniques for analyzing the kinds of studies typically reported in Circulation Research are described. Particular emphasis is given to the comparison of means from more than two populations, the joint effect of several experimentally controlled variables, and the analysis of studies with repeated measurements on the same experimental units.

Tóm tắt —Bằng chứng tích lũy cho thấy stress oxy hóa làm thay đổi nhiều chức năng của nội mô, bao gồm cả sự điều hòa trương lực mạch. Sự bất hoạt của nitric oxide (NO ^· ) bởi superoxide và các gốc oxy hóa mạnh khác (ROS) dường như xảy ra trong các điều kiện như tăng huyết áp, tăng cholesterol máu, tiểu đường, và hút thuốc lá. Mất NO ^· liên quan đến các yếu tố nguy cơ truyền thống này có thể phần nào giải thích tại sao chúng gây ra xơ vữa động mạch. Trong số nhiều hệ thống enzyme có khả năng sinh ra ROS, xanthine oxidase, NADH/NADPH oxidase, và synthase nitric oxide nội mô không ghép cóp đã được nghiên cứu kỹ lưỡng trong các tế bào mạch máu. Khi vai trò của các nguồn enzyme ROS khác nhau này trở nên rõ ràng, có thể sẽ có thể sử dụng các phương pháp điều trị cụ thể hơn để ngăn chặn sự sản sinh của chúng và cuối cùng là chỉnh sửa rối loạn chức năng nội mô.

Abstract —Circulating endothelial progenitor cells (EPCs) have been isolated in peripheral blood of adult species. To determine the origin and role of EPCs contributing to postnatal vasculogenesis, transgenic mice constitutively expressing β-galactosidase under the transcriptional regulation of an endothelial cell–specific promoter (Flk-1/LZ or Tie-2/LZ) were used as transplant donors. Localization of EPCs, indicated by flk-1 or tie-2/lacZ fusion transcripts, were identified in corpus luteal and endometrial neovasculature after inductive ovulation. Mouse syngeneic colon cancer cells (MCA38) were implanted subcutaneously into Flk-1/LZ/BMT (bone marrow transplantation) and Tie-2/LZ/BMT mice; tumor samples harvested at 1 week disclosed abundant flk-1/lacZ and tie-2/lacZ fusion transcripts, and sections stained with X-gal demonstrated that the neovasculature of the developing tumor frequently comprised Flk-1– or Tie-2–expressing EPCs. Cutaneous wounds examined at 4 days and 7 days after skin removal by punch biopsy disclosed EPCs incorporated into foci of neovascularization at high frequency. One week after the onset of hindlimb ischemia, lacZ-positive EPCs were identified incorporated into capillaries among skeletal myocytes. After permanent ligation of the left anterior descending coronary artery, histological samples from sites of myocardial infarction demonstrated incorporation of EPCs into foci of neovascularization at the border of the infarct. These findings indicate that postnatal neovascularization does not rely exclusively on sprouting from preexisting blood vessels (angiogenesis); instead, EPCs circulate from bone marrow to incorporate into and thus contribute to postnatal physiological and pathological neovascularization, which is consistent with postnatal vasculogenesis.

Abstract —Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The biochemical characterization, activation paradigms, structure, and function of this enzyme are now partly understood. Vascular NAD(P)H oxidases share some, but not all, characteristics of the neutrophil enzyme. In response to growth factors and cytokines, they produce superoxide, which is metabolized to hydrogen peroxide, and both of these reactive oxygen species serve as second messengers to activate multiple intracellular signaling pathways. The vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.

Dysfunction of the endothelial lining of lesion-prone areas of the arterial vasculature is an important contributor to the pathobiology of atherosclerotic cardiovascular disease. Endothelial cell dysfunction, in its broadest sense, encompasses a constellation of various nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone and redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. In this review, we trace the evolution of the concept of endothelial cell dysfunction, focusing on recent insights into the cellular and molecular mechanisms that underlie its pivotal roles in atherosclerotic lesion initiation and progression; explore its relationship to classic, as well as more recently defined, clinical risk factors for atherosclerotic cardiovascular disease; consider current approaches to the clinical assessment of endothelial cell dysfunction; and outline some promising new directions for its early detection and treatment.

Infusion of different hematopoietic stem cell populations and ex vivo expanded endothelial progenitor cells augments neovascularization of tissue after ischemia and contributes to reendothelialization after endothelial injury, thereby, providing a novel therapeutic option. However, controversy exists with respect to the identification and the origin of endothelial progenitor cells. Overall, there is consensus that endothelial progenitor cells can derive from the bone marrow and that CD133/VEGFR2 cells represent a population with endothelial progenitor capacity. However, increasing evidence suggests that there are additional bone marrow-derived cell populations (eg, myeloid cells, “side population” cells, and mesenchymal cells) and non-bone marrow-derived cells, which also can give rise to endothelial cells. The characterization of the different progenitor cell populations and their functional properties are discussed. Mobilization and endothelial progenitor cell-mediated neovascularization is critically regulated. Stimulatory (eg, statins and exercise) or inhibitory factors (risk factors for coronary artery disease) modulate progenitor cell levels and, thereby, affect the vascular repair capacity. Moreover, recruitment and incorporation of endothelial progenitor cells requires a coordinated sequence of multistep adhesive and signaling events including adhesion and migration (eg, by integrins), chemoattraction (eg, by SDF-1/CXCR4), and finally the differentiation to endothelial cells. This review summarizes the mechanisms regulating endothelial progenitor cell-mediated neovascularization and reendothelialization.