Inhibition of STAT3 signaling prevents vascular smooth muscle cell proliferation and neointima formation

Dedifferentiation, migration, and proliferation of resident vascular smooth muscle cells (SMCs) are key components of neointima formation after vascular injury. Activation of signal transducer and activator of transcription-3 (STAT3) is suggested to be critically involved in this process, but the complex regulation of STAT3-dependent genes and the functional significance of inhibiting this pathway during the development of vascular proliferative diseases remain elusive. In this study, we demonstrate that STAT3 was activated in neointimal lesions following wire-induced injury in mice. Phosphorylation of STAT3 induced trans-activation of cyclin D1 and survivin in SMCs in vitro and in neointimal cells in vivo, thus promoting proliferation and migration of SMCs as well as reducing apoptotic cell death. WP1066, a highly potent inhibitor of STAT3 signaling, abrogated phosphorylation of STAT3 and dose-dependently inhibited the functional effects of activated STAT3 in stimulated SMCs. The local application of WP1066 via a thermosensitive pluronic F-127 gel around the dilated arteries significantly inhibited proliferation of neointimal cells and decreased the neointimal lesion size at 3 weeks after injury. Even though WP1066 application attenuated the injury-induced up-regulation of the chemokine RANTES at 6 h after injury, there was no significant effect on the accumulation of circulating cells at 1 week after injury. In conclusion, these data identify STAT3 as a key molecule for the proliferative response of SMC and neointima formation. Moreover, inhibition of STAT3 by the potent and specific compound WP1066 might represent a novel and attractive approach for the local treatment of vascular proliferative diseases

miR-92a – a key player in cardiovascular remodeling: DOI: 10.14800/rd.371

  Small non-coding, highly conserved microRNAs (miRs) play a crucial role in gene regulation, especially in post-transcriptional gene silencing, and are important for vascular homeostasis as well as during pathophysiological vascular remodeling processes. miR-92a is a known negative regulator of endothelial cell proliferation, angiogenesis and vascular repair. Conversely, inhibition of miR-92a improves angiogenesis in models of hind limb- or myocardial ischemia. We recently showed that inhibition of miR-92a using specific locked nucleic acid-based antimiRs accelerates the re-endothelialization process and prevents neointimal lesion formation following wire-induced injury of murine femoral arteries. Thus, miR-92a inhibitors may represent promising therapeutic tools for the treatment of vascular diseases

Focus Topic:Decision-Making Regarding Resuscitation from Cardiac Arrest in the ICU

Cardiopulmonary resuscitation (CPR) in intensive care units (ICUs) differs in several ways from treatment of a cardiac arrest occurring outside the hospital or in other areas of the hospital, not only in the availability of advanced invasive treatment options (such as extracorporeal life support) but also in pre-existing conditions and severity of illness which may make prognostication more difficult. In addition, patients in the ICU are often receiving substantial levels of life-supporting therapies when arrest occurs, and thus CPR may have minimal prospects of success. Application of the ethical principles beneficence, maleficence, autonomy, and (distributive) justice as well as careful consideration of the treatment pillars “medical indication” and “patient’s consent” is therefore a special challenge, especially in relation to withholding or terminating resuscitative attempts. Following these principles, this chapter spotlights the topics “slow codes,” “do not attempt resuscitation” orders, and the special challenges of extracorporeal CPR.</p

Focus Topic:Decision-Making Regarding Resuscitation from Cardiac Arrest in the ICU

Cardiopulmonary resuscitation (CPR) in intensive care units (ICUs) differs in several ways from treatment of a cardiac arrest occurring outside the hospital or in other areas of the hospital, not only in the availability of advanced invasive treatment options (such as extracorporeal life support) but also in pre-existing conditions and severity of illness which may make prognostication more difficult. In addition, patients in the ICU are often receiving substantial levels of life-supporting therapies when arrest occurs, and thus CPR may have minimal prospects of success. Application of the ethical principles beneficence, maleficence, autonomy, and (distributive) justice as well as careful consideration of the treatment pillars “medical indication” and “patient’s consent” is therefore a special challenge, especially in relation to withholding or terminating resuscitative attempts. Following these principles, this chapter spotlights the topics “slow codes,” “do not attempt resuscitation” orders, and the special challenges of extracorporeal CPR.</p

Isolation of circulating endothelial cells provides tool to determine endothelial cell senescence in blood samples

Abstract Circulating endothelial cells (CEC) are arising as biomarkers for vascular diseases. However, whether they can be utilized as markers of endothelial cell (EC) senescence in vivo remains unknown. Here, we present a protocol to isolate circulating endothelial cells for a characterization of their senescent signature. Further, we characterize different models of EC senescence induction in vitro and show similar patterns of senescence being upregulated in CECs of aged patients as compared to young volunteers. Replication-(ageing), etoposide-(DNA damage) and angiotensin II-(ROS) induced senescence models showed the expected cell morphology and proliferation-reduction effects. Expression of senescence-associated secretory phenotype markers was specifically upregulated in replication-induced EC senescence. All models showed reduced telomere lengths and induction of the INK4a/ARF locus. Additional p14ARF-p21 pathway activation was observed in replication- and etoposide-induced EC senescence. Next, we established a combined magnetic activated- and fluorescence activated cell sorting (MACS-FACS) based protocol for CEC isolation. Interestingly, CECs isolated from aged volunteers showed similar senescence marker patterns as replication- and etoposide-induced senescence models. Here, we provide first proof of senescence in human blood derived circulating endothelial cells. These results hint towards an exciting future of using CECs as mirror cells for in vivo endothelial cell senescence, of particular interest in the context of endothelial dysfunction and cardiovascular diseases

Vasa Vasorum Angiogenesis: Key Player in the Initiation and Progression of Atherosclerosis and Potential Target for the Treatment of Cardiovascular Disease

Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes

Vasa Vasorum Angiogenesis: Key Player in the Initiation and Progression of Atherosclerosis and Potential Target for the Treatment of Cardiovascular Disease

Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes

Verantwortlicher Umgang mit ICDs. Stellungnahme der Deutschen Gesellschaft für Kardiologie und ihrer Schwester-Gesellschaften

Responsible handling of ICDs Statement of the German Society of Cardiology and sister societies Abstract An increasing number of patients receive small implantable cardioverter/defibrillators (ICDs) embedded under their skin so as to prevent potentially life-threatening cardiac arrhythmias. As beneficial as these devices may be, they can also trigger problems, particularly when patients approach the end of life independent of their concomitant heart disease. In such cases, often many years after the initial implantation, ICDs may burden patients by unwanted shocks and by prolonging the process of dying. Fortunately, these problems can be eliminated by an ICD deactivation from outside, based on the patient’s (presumed) consent. Treating physicians, however, must be well acquainted with both the technical feasibility and equipment as well as the legal and ethical permissibility of such deactivations. Moreover, it is within the physicians’ responsibility to inform patients about these problems and their possible handling by an ICD directive in the context of advance care planning. The following report provides a systematic analysis of the aforementioned aspects as well as practical recommendations