Rationale:: MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications. Objective:: In this study, we explore plasma miRNA profiles in patients with DM. Methods and Results:: Total RNA was extracted from plasma samples of the prospective population-based Bruneck study. A total of 13 candidate miRNAs identified by microarray screening and miRNA network inference were quantified by quantitative PCR in all diabetic patients of the Bruneck study and age- and sex-matched controls (1995 evaluation, n=80 each). Quantitative PCR assessment revealed lower plasma levels of miR-20b, miR-21, miR-24, miR-15a, miR-126, miR-191, miR-197, miR-223, miR-320, and miR-486 in prevalent DM, but a modest increase of miR-28-3p. Findings emerged as robust in multivariable analysis and were independent of the standardization procedure applied. For endothelial miR-126, results were confirmed in the entire Bruneck cohort (n=822) in univariate (odds ratio [95% confidence interval], 0.38 [0.26 to 0.55]; P =2.72×10 ⁻⁷ ) and multivariate analyses (0.57 [0.37 to 0.86]; P =0.0082). Importantly, reduced miR-15a, miR-29b, miR-126, miR-223, and elevated miR-28-3p levels antedated the manifestation of disease. Most differences in miRNA levels were replicated in plasma obtained from hyperglycemic Lep ^ob mice. High glucose concentrations reduced the miR-126 content of endothelial apoptotic bodies. Similarly in patients with DM, the reduction of miR-126 was confined to circulating vesicles in plasma. Conclusions:: We reveal a plasma miRNA signature for DM that includes loss of endothelial miR-126. These findings might explain the impaired peripheral angiogenic signaling in patients with DM.

Peripartum cardiomyopathy (PPCM) is a cause of pregnancy-associated heart failure. It typically develops during the last month of, and up to 6 months after, pregnancy in women without known cardiovascular disease. The present position statement offers a state-of-the-art summary of what is known about risk factors for potential pathophysiological mechanisms, clinical presentation of, and diagnosis and management of PPCM. A high index of suspicion is required for the diagnosis, as shortness of breath and ankle swelling are common in the peripartum period. Peripartum cardiomyopathy is a distinct form of cardiomyopathy, associated with a high morbidity and mortality, but also with the possibility of full recovery. Oxidative stress and the generation of a cardiotoxic subfragment of prolactin may play key roles in the pathophysiology of PPCM. In this regard, pharmacological blockade of prolactin offers the possibility of a disease-specific therapy.

Rationale:: The function of Nox4, a source of vascular H ₂ O ₂ , is unknown. Other Nox proteins were identified as mediators of endothelial dysfunction. Objective:: We determined the function of Nox4 in situations of increased stress induced by ischemia or angiotensin II with global and tamoxifen-inducible Nox4 ^−/− mice. Methods and Results:: Nox4 was highly expressed in the endothelium and contributed to H ₂ O ₂ formation. Nox4 ^−/− mice exhibited attenuated angiogenesis (femoral artery ligation) and PEG-catalase treatment in control mice had a similar effect. Tube formation in cultured Nox4 ^−/− lung endothelial cells (LECs) was attenuated and restored by low concentrations of H ₂ O _2, whereas PEG-catalase attenuated tube formation in control LECs. Angiotensin II infusion was used as a model of oxidative stress. Compared to wild-type, aortas from inducible Nox4-deficient animals had development of increased inflammation, media hypertrophy, and endothelial dysfunction. Mechanistically, loss of Nox4 resulted in reduction of endothelial nitric oxide synthase expression, nitric oxide production, and heme oxygenase-1 (HO-1) expression, which was associated with apoptosis and inflammatory activation. HO-1 expression is controlled by Nrf-2. Accordingly, Nox4-deficient LECs exhibited reduced Nrf-2 protein level and deletion of Nox4 reduced Nrf-2 reporter gene activity. In vivo treatment with hemin, an inducer of HO-1, blocked the vascular hypertrophy induced by Nox4 deletion in the angiotensin II infusion model and carbon monoxide, the product of HO-1, blocked the Nox4-deletion-induced apoptosis in LECs. Conclusion:: Endogenous Nox4 protects the vasculature during ischemic or inflammatory stress. Different from Nox1 and Nox2, this particular NADPH oxidase therefore may have a protective vascular function.

The endothelial generation of reactive oxygen species (ROS) is important both physiologically and in the pathogenesis of many cardiovascular disorders. ROS generated by endothelial cells include superoxide (O₂⁻·), hydrogen peroxide (H₂O₂), peroxynitrite (ONOO⁻·), nitric oxide (NO), and hydroxyl (·OH) radicals. The O₂⁻· radical, the focus of the current review, may have several effects either directly or through the generation of other radicals, e.g., H₂O₂and ONOO⁻·. These effects include 1) rapid inactivation of the potent signaling molecule and endothelium-derived relaxing factor NO, leading to endothelial dysfunction; 2) the mediation of signal transduction leading to altered gene transcription and protein and enzyme activities (“redox signaling”); and 3) oxidative damage. Multiple enzymes can generate O₂⁻·, notably xanthine oxidase, uncoupled NO synthase, and mitochondria. Recent studies indicate that a major source of endothelial O₂⁻· involved in redox signaling is a multicomponent phagocyte-type NADPH oxidase that is subject to specific regulation by stimuli such as oscillatory shear stress, hypoxia, angiotensin II, growth factors, cytokines, and hyperlipidemia. Depending on the level of oxidants generated and the relative balance between pro- and antioxidant pathways, ROS may be involved in cell growth, hypertrophy, apoptosis, endothelial activation, and adhesivity, for example, in diabetes, hypertension, atherosclerosis, heart failure, and ischemia-reperfusion. This article reviews our current knowledge regarding the sources of endothelial ROS generation, their regulation, their involvement in redox signaling, and the relevance of enhanced ROS generation and redox signaling to the pathophysiology of cardiovascular disorders where endothelial activation and dysfunction are implicated.

Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart. However, maladaptive immune cell behaviour contributes to ventricular remodelling in mouse models, prompting experimental efforts to modulate the immune response to prevent the development of HF. Seminal work in macrophage biology defined macrophages as monocyte-derived cells that are comprised of two populations, pro-inflammatory M1 macrophages and reparative M2 macrophages, and initial investigations into cardiac macrophage populations following AMI suggested they aligned well to this model. However, more recent data, in the heart and other tissues, demonstrate remarkable heterogeneity and plasticity in macrophage development, phenotype, and function. These recent insights into macrophage biology may explain the failure of non-specific immunosuppressive strategies and offer novel opportunities for therapeutic targeting to prevent HF following AMI. Here, we summarize the traditional monocyte-macrophage paradigm, experimental evidence for the significance of these cells in HF after AMI, and the potential relevance of emerging evidence that refutes canonical models of monocyte and macrophage biology.