Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE-/- mice.

Airway exposure to eg particulate matter is associated with cardiovascular disease including atherosclerosis. Acute phase genes, especially Serum Amyloid A3 (Saa3), are highly expressed in the lung following pulmonary exposure to particles. We aimed to investigate whether the human acute phase protein SAA (a homolog to mouse SAA3) accelerated atherosclerotic plaque progression in Apolipoprotein E knockout (ApoE-/- ) mice. Mice were intratracheally (i.t.) instilled with vehicle (phosphate buffered saline) or 2 µg human SAA once a week for 10 weeks. Plaque progression was assessed in the aorta using noninvasive ultrasound imaging of the aorta arch as well as by en face analysis. Additionally, lipid peroxidation, SAA3, and cholesterol were measured in plasma, inflammation was determined in lung, and mRNA levels of the acute phase genes Saa1 and Saa3 were measured in the liver and lung, respectively. Repeated i.t. instillation with SAA caused a significant progression in the atherosclerotic plaques in the aorta (1.5-fold). Concomitantly, SAA caused a statistically significant increase in neutrophils in bronchoalveolar lavage fluid (625-fold), in pulmonary Saa3 (196-fold), in systemic SAA3 (1.8-fold) and malondialdehyde levels (1.14-fold), indicating acute phase response (APR), inflammation and oxidative stress. Finally, pulmonary exposure to SAA significantly decreased the plasma levels of very low-density lipoproteins - low-density lipoproteins and total cholesterol, possibly due to lipids being sequestered in macrophages or foam cells in the arterial wall. Combined these results indicate the importance of the pulmonary APR and SAA3 for plaque progression.

KCNMA1 encoded cardiac BK channels afford protection against ischemia-reperfusion injury.

Mitochondrial potassium channels have been implicated in myocardial protection mediated through pre-/postconditioning. Compounds that open the Ca2+- and voltage-activated potassium channel of big-conductance (BK) have a pre-conditioning-like effect on survival of cardiomyocytes after ischemia/reperfusion injury. Recently, mitochondrial BK channels (mitoBKs) in cardiomyocytes were implicated as infarct-limiting factors that derive directly from the KCNMA1 gene encoding for canonical BKs usually present at the plasma membrane of cells. However, some studies challenged these cardio-protective roles of mitoBKs. Herein, we present electrophysiological evidence for paxilline- and NS11021-sensitive BK-mediated currents of 190 pS conductance in mitoplasts from wild-type but not BK-/- cardiomyocytes. Transmission electron microscopy of BK-/- ventricular muscles fibres showed normal ultra-structures and matrix dimension, but oxidative phosphorylation capacities at normoxia and upon re-oxygenation after anoxia were significantly attenuated in BK-/- permeabilized cardiomyocytes. In the absence of BK, post-anoxic reactive oxygen species (ROS) production from cardiomyocyte mitochondria was elevated indicating that mitoBK fine-tune the oxidative state at hypoxia and re-oxygenation. Because ROS and the capacity of the myocardium for oxidative metabolism are important determinants of cellular survival, we tested BK-/- hearts for their response in an ex-vivo model of ischemia/reperfusion (I/R) injury. Infarct areas, coronary flow and heart rates were not different between wild-type and BK-/- hearts upon I/R injury in the absence of ischemic pre-conditioning (IP), but differed upon IP. While the area of infarction comprised 28±3% of the area at risk in wild-type, it was increased to 58±5% in BK-/- hearts suggesting that BK mediates the beneficial effects of IP. These findings suggest that cardiac BK channels are important for proper oxidative energy supply of cardiomyocytes at normoxia and upon re-oxygenation after prolonged anoxia and that IP might indeed favor survival of the myocardium upon I/R injury in a BK-dependent mode stemming from both mitochondrial post-anoxic ROS modulation and non-mitochondrial localizations.

Attenuated ventricular ß-adrenergic response and reduced repolarization reserve in a rabbit model of chronic heart failure.

Animal models of pacing-induced heart failure (HF) are often associated with high acute mortality secondary to high pacing frequencies. The present study therefore exploits lower-frequency left ventricular pacing (300 beats per minute) in rabbits for 11 weeks to produce chronic HF with low acute mortality but profound structural, functional, and electrical remodeling and compare with nonpaced controls. Pacing increased heart weight/body weight ratio and decreased left ventricular fractional shortening in tachypaced only. Electrocardiogram recordings during sinus rhythm revealed QTc prolongation in paced animals. Ventricular arrhythmias or sudden death was not observed. Isoproterenol increased heart rate similarly in both groups but showed a blunted QT-shortening effect in tachypaced rabbits compared with controls. Langendorff experiments revealed significant monophasic action potential duration prolongation in tachypaced hearts and reduced contractility at cycle lengths from 400 to 250 ms. Hyperkalemia caused monophasic action potential duration shortening in controls, whereas crossover was seen in tachypaced with monophasic action potential duration prolongation at short cycle length. Hypokalemia prolonged monophasic action potential duration and increased short-term variability of repolarization in tachypaced hearts. A blunted monophasic action potential duration response was observed ex vivo in tachypaced hearts after isoproterenol. The HF rabbits showed structural, functional, and electrical remodeling but very low mortality. Isokalemic and hyperkalemic responses indicate downregulation of functional IKs. Increased short-term variability during hypokalemia unmasks a reduced repolarization reserve.