Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction

BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the α-myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI

The relevance of tissue angiotensin-converting enzyme: manifestations in mechanistic and endpoint data

Angiotensin-converting enzyme (ACE) is primarily localized (>90%) in various tissues and organs, most notably on the endothelium but also within parenchyma and inflammatory cells. Tissue ACE is now recognized as a key factor in cardiovascular and renal diseases. Endothelial dysfunction, in response to a number of risk factors or injury such as hypertension, diabetes mellitus, hypercholesteremia, and cigarette smoking, disrupts the balance of vasodilation and vasoconstriction, vascular smooth muscle cell growth, the inflammatory and oxidative state of the vessel wall, and is associated with activation of tissue ACE. Pathologic activation of local ACE can have deleterious effects on the heart, vasculature, and the kidneys. The imbalance resulting from increased local formation of angiotensin II and increased bradykinin degradation favors cardiovascular disease. Indeed, ACE inhibitors effectively reduce high blood pressure and exert cardio- and renoprotective actions. Recent evidence suggests that a principal target of ACE inhibitor action is at the tissue sites. Pharmacokinetic properties of various ACE inhibitors indicate that there are differences in their binding characteristics for tissue ACE. Clinical studies comparing the effects of antihypertensives (especially ACE inhibitors) on endothelial function suggest differences. More comparative experimental and clinical studies should address the significance of these drug differences and their impact on clinical events

From Vulnerable Plaque to Vulnerable Patient

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients

A Flying Platform to Investigate Neuronal Correlates of Navigation in the Honey Bee (Apis mellifera)

Navigating animals combine multiple perceptual faculties, learn during exploration, retrieve multi-facetted memory contents, and exhibit goal-directedness as an expression of their current needs and motivations. Navigation in insects has been linked to a variety of underlying strategies such as path integration, view familiarity, visual beaconing, and goal-directed orientation with respect to previously learned ground structures. Most works, however, study navigation either from a field perspective, analyzing purely behavioral observations, or combine computational models with neurophysiological evidence obtained from lab experiments. The honey bee (Apis mellifera) has long been a popular model in the search for neural correlates of complex behaviors and exhibits extraordinary navigational capabilities. However, the neural basis for bee navigation has not yet been explored under natural conditions. Here, we propose a novel methodology to record from the brain of a copter-mounted honey bee. This way, the animal experiences natural multimodal sensory inputs in a natural environment that is familiar to her. We have developed a miniaturized electrophysiology recording system which is able to record spikes in the presence of time-varying electric noise from the copter's motors and rotors, and devised an experimental procedure to record from mushroom body extrinsic neurons (MBENs). We analyze the resulting electrophysiological data combined with a reconstruction of the animal's visual perception and find that the neural activity of MBENs is linked to sharp turns, possibly related to the relative motion of visual features. This method is a significant technological step toward recording brain activity of navigating honey bees under natural conditions. By providing all system specifications in an online repository, we hope to close a methodological gap and stimulate further research informing future computational models of insect navigation

Oxidant stress impairs in vivo reendothelialization capacity of endothelial progenitor cells from patients with type 2 diabetes mellitus: restoration by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone

BACKGROUND: Endothelial progenitor cells (EPCs) are thought to contribute to endothelial recovery after arterial injury. We therefore compared in vivo reendothelialization capacity of EPCs derived from patients with diabetes mellitus and healthy subjects. Moreover, we examined the effect of treatment with the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone on oxidant stress, nitric oxide (NO) bioavailability, and the in vivo reendothelialization capacity of EPCs from diabetic individuals. METHODS AND RESULTS: In vivo reendothelialization capacity of EPCs from diabetic patients (n=30) and healthy subjects (n=10) was examined in a nude mouse carotid injury model. Superoxide and NO production of EPCs was determined by electron spin resonance spectroscopy. Thirty patients with diabetes mellitus were randomized to 2 weeks of rosiglitazone (4 mg BID p.o.) or placebo treatment. In vivo reendothelialization capacity of EPCs derived from diabetic subjects was severely reduced compared with EPCs from healthy subjects (reendothelialized area: 8+/-3% versus 37+/-10%; P<0.001). EPCs from diabetic individuals had a substantially increased superoxide production and impaired NO bioavailability. Small-interfering RNA silencing of NAD(P)H oxidase subunit p47(phox) reduced superoxide production and restored NO bioavailability and in vivo reendothelialization capacity of EPCs from diabetic patients. Importantly, rosiglitazone therapy normalized NAD(P)H oxidase activity, restored NO bioavailability, and improved in vivo reendothelialization capacity of EPCs from diabetic patients (reendothelialized area: placebo versus rosiglitazone, 8+/-1% versus 38+/-5%; P<0.001). CONCLUSIONS: In vivo reendothelialization capacity of EPCs derived from individuals with diabetes mellitus is severely impaired at least partially as a result of increased NAD(P)H oxidase-dependent superoxide production and subsequently reduced NO bioavailability. Rosiglitazone therapy reduces NAD(P)H oxidase activity and improves reendothelialization capacity of EPCs from diabetic individuals, representing a potential novel mechanism whereby peroxisome proliferator-activated receptor-gamma agonism promotes vascular repair