Through modulation of cardiac Ca2+ handling, UCP2 affects cardiac electrophysiology and influences the susceptibility for Ca2+ -mediated arrhythmias.

NEW FINDINGS: What is the central question of this study? Knockdown of UCP2 reduces mitochondrial Ca2+ uptake. This suggests that Ucp2 knockout mice need to have additional effects on cytosolic Ca2+ handling to prevent Ca2+ overload. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. What is the main finding and its importance? In Ucp2 knockout mice, decreased mitochondrial Ca2+ uptake is compensated for by functional inhibition of L-type Ca2+ channels and resultant shortening of action potential duration. UCP2-dependent modulations have a major impact on cardiac electrophysiology, resulting in alterations of ECG characteristics and a higher susceptibility to Ca2+ -mediated ventricular arrhythmias. Uncoupling protein 2 (mitochondrial, proton carrier) (UCP2) belongs to a superfamily of mitochondrial ion transporters. Owing to its beneficial influence on production of reactive oxygen species, it is suggested to reduce cardiac ischaemia-reperfusion injury. Recent studies have uncovered its ability to regulate mitochondrial Ca2+ uptake and therefore to influence cardiac cytosolic Ca2+ handling, indicating compensatory pathways to avoid toxic Ca2+ overload in Ucp2 knockout (Ucp2-/- ) mice. However, the specific mechanisms and their impact on cardiac electrophysiology remain speculative. Molecular analyses, whole-cell patch clamp in cardiomyocytes and ECG studies were performed in Ucp2-/- and wild-type (WT) control mice. Furthermore, to explore the impact on cardiac arrhythmogenicity, ECG monitoring was performed in basal conditions and during Ca2+ -mediated stress using Bay K 8644. Although cardiac ryanodine receptor 2, NCX1, L-type Ca2+ channel (LTCC) and SERCA2a expression were not altered, Ucp2-/- mice revealed major variations in cardiac electrophysiology. The LTCC current and APD90 were decreased in Ucp2-/- mice, indicating compensatory mechanisms. Furthermore, in Ucp2-/- mice, an increased slope factor of action potential upstrokes and more hyperpolarized resting membrane potential were measured, suggesting variations in cardiac excitability. In agreement with alterations of cellular physiology in Ucp2-/- mice, reductions in PR and QRS as well as shortening of the QTc interval were noted in ECG recordings. Importantly, an increased incidence of cellular after-depolarizations and more pronounced susceptibility to Ca2+ -mediated arrhythmias were observed. Furthermore, although expression of UCP3 was not different, levels of PRMT1 were significantly higher in Ucp2-/- mice. Our observations indicate compensatory mechanisms by which Ucp2-/- mice prevent toxic cytosolic Ca2+ overload. UCP2-dependent modulations have a major impact on cardiac electrophysiology and influence susceptibility to Ca2+ -mediated ventricular arrhythmias.

Characteristics of coronary artery disease among patients with atrial fibrillation compared to patients with sinus rhythm.

BACKGROUND: With a high prevalence of coronary artery disease (CAD) among patients with atrial fibrillation (AF), CAD is one of the main risk factors for AF. However, little is known about the characteristics of CAD in AF patients, especially whether a specific anatomical distribution of coronary artery stenoses might predispose an individual to AF via atrial ischemia remains speculative. To address this issue, we evaluated the potential associations between angiographic characteristics of CAD and AF. METHODS: In this single-center retrospective analysis, 796 consecutive patients with confirmed CAD and AF (CAD-AF) and 785 patients with CAD and sinus rhythm (CAD-SR) were enrolled. Clinical characteristics and angiographic findings were compared between groups in stable CAD and during acute myocardial infarction (MI). RESULTS: Mitral valve disease and chronic heart failure were significantly more common in CAD-AF than in CAD-SR. Clinical condition in CAD-AF was significantly more severe as indicated by New York Heart Association/World Health Organization functional class. Left ventricular ejection fraction was reduced in CAD-AF, reflecting the marked fraction of patients with ischemic cardiomyopathy. No association between anatomical characteristics of CAD and AF was found. However, CAD-AF seemed to be associated with a higher CAD severity (p = 0.06). Additionally, CAD-AF with MI showed a significantly higher number of diseased coronary vessels. CONCLUSION: The anatomical distribution of coronary artery stenoses does not contribute to AF in CAD patients. However, AF is linked to a higher CAD severity, which might predispose individuals to AF by driving ischemic heart disease and changes in left ventricular function.

Aquaporin expression and localization in the rabbit eye.

Aquaporins (AQPs) are important for ocular homeostasis and function. While AQP expression has been investigated in ocular tissues of human, mouse, rat and dog, comprehensive data in rabbits are missing. As rabbits are frequently used model organisms in ophthalmic research, the aim of this study was to analyze mRNA expression and to localize AQPs in the rabbit eye. The results were compared with the data published for other species. In cross sections of New Zealand White rabbit eyes AQP0 to AQP5 were labeled by immunohistology and analyzed by confocal microscopy. Immunohistological findings were compared to mRNA expression levels, which were analyzed by quantitative reverse transcription real time polymerase chain reaction (qRT-PCR). The primers used were homologous against conserved regions of AQPs. In the rabbit eye, AQP0 protein expression was restricted to the lens, while AQP1 was present in the cornea, the chamber angle, the iris, the ciliary body, the retina and, to a lower extent, in optic nerve vessels. AQP3 and AQP5 showed immunopositivity in the cornea. AQP3 was also present in the conjunctiva, which could not be confirmed for AQP5. However, at a low level AQP5 was also traceable in the lens. AQP4 protein was detected in the ciliary non-pigmented epithelium (NPE), the retina, optic nerve astrocytes and extraocular muscle fibers. For most tissues the qRT-PCR data confirmed the immunohistology results and vice versa. Although species differences exist, the AQP protein expression pattern in the rabbit eye shows that, especially in the anterior section, the AQP distribution is very similar to human, mouse, rat and dog. Depending on the ocular regions investigated in rabbit, different protein and mRNA expression results were obtained. This might be caused by complex gene regulatory mechanisms, post-translational protein modifications or technical limitations. However, in conclusion the data suggest that the rabbit is a useful in-vivo model to study AQP function and the effects of direct and indirect intervention strategies to investigate e. g. mechanisms for intraocular pressure modulation or cornea transparency regulation.

Brain and Retinal Pericytes: Origin, Function and Role.

Pericytes are specialized mural cells located at the abluminal surface of capillary blood vessels, embedded within the basement membrane. In the vascular network these multifunctional cells fulfil diverse functions, which are indispensable for proper homoeostasis. They serve as microvascular stabilizers, are potential regulators of microvascular blood flow and have a central role in angiogenesis, as they for example regulate endothelial cell proliferation. Furthermore, pericytes, as part of the neurovascular unit, are a major component of the blood-retina/brain barrier. CNS pericytes are a heterogenic cell population derived from mesodermal and neuro-ectodermal germ layers acting as modulators of stromal and niche environmental properties. In addition, they display multipotent differentiation potential making them an intriguing target for regenerative therapies. Pericyte-deficiencies can be cause or consequence of many kinds of diseases. In diabetes, for instance, pericyte-loss is a severe pathological process in diabetic retinopathy (DR) with detrimental consequences for eye sight in millions of patients. In this review, we provide an overview of our current understanding of CNS pericyte origin and function, with a special focus on the retina in the healthy and diseased. Finally, we highlight the role of pericytes in de- and regenerative processes.