Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signalregulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK ؊/؊ ) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK ؊/؊ hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK ؊/؊ had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK ؊/؊ compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK ؊/؊ cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis.

The molecular mechanism for the transition from cardiac hypertrophy, an adaptive response to biomechanical stress, to heart failure is poorly understood. The mitogen-activated protein kinase p38␣ is a key component of stress response pathways in various types of cells. In this study, we attempted to explore the in vivo physiological functions of p38␣ in hearts. First, we generated mice with floxed p38␣ alleles and crossbred them with mice expressing the Cre recombinase under the control of the ␣-myosin heavy-chain promoter to obtain cardiac-specific p38␣ knockout mice. These cardiac-specific p38␣ knockout mice were born normally, developed to adulthood, were fertile, exhibited a normal life span, and displayed normal global cardiac structure and function. In response to pressure overload to the left ventricle, they developed significant levels of cardiac hypertrophy, as seen in controls, but also developed cardiac dysfunction and heart dilatation. This abnormal response to pressure overload was accompanied by massive cardiac fibrosis and the appearance of apoptotic cardiomyocytes. These results demonstrate that p38␣ plays a critical role in the cardiomyocyte survival pathway in response to pressure overload, while cardiac hypertrophic growth is unaffected despite its dramatic down-regulation.

Sarcolipin (SLN) inhibits the cardiac sarco(endo)plasmic reticulum Ca 2؉ ATPase (SERCA2a) by direct binding and is superinhibitory if it binds through phospholamban (PLN). To determine whether overexpression of SLN in the heart might impair cardiac function, transgenic (TG) mice were generated with cardiac-specific overexpression of NF-SLN (SLN tagged at its N terminus with the FLAG epitope). The level of NF-SLN expression (the NF-SLN͞PLN expression ratio) was equivalent to that which induces profound superinhibition when coexpressed with PLN and SERCA2a in HEK-293 cells. In TG hearts, the apparent affinity of SERCA2a for Ca 2؉ was decreased compared with non-TG littermate control hearts. Invasive hemodynamic and echocardiographic analyses revealed impaired cardiac contractility and ventricular hypertrophy in TG mice. Basal PLN phosphorylation was reduced. In isolated papillary muscle subjected to isometric tension, peak amplitudes of Ca 2؉ transients and peak tensions were reduced, whereas decay times of Ca 2؉ transients and relaxation times of tension were increased in TG mice. Isoproterenol largely restored contractility in papillary muscle and stimulated PLN phosphorylation to wild-type levels in intact hearts. No compensatory changes in expression of SERCA2a, PLN, ryanodine receptor, and calsequestrin were observed in TG hearts. Coimmunoprecipitation indicated that overexpressed NF-SLN was bound to both SERCA2a and PLN, forming a ternary complex. These data suggest that NF-SLN overexpression inhibits SERCA2a through stabilization of SERCA2a-PLN interaction in the absence of PLN phosphorylation and through the inhibition of PLN phosphorylation. Inhibition of SERCA2a impairs contractility and calcium cycling, but responsiveness to ␤-adrenergic agonists may prevent progression to heart failure. to the extracellular space. SERCA2a is regulated by phospholamban (PLN) and can potentially be regulated by a homologous protein, sarcolipin (SLN) (1, 2).PLN is a 52-aa SR membrane protein expressed abundantly in cardiac muscle (3). In its dephosphorylated form, PLN interacts with SERCA2a to inhibit Ca 2ϩ transport by lowering the apparent affinity of SERCA2a for Ca 2ϩ . When PLN is phosphorylated, its inhibitory effect on SERCA2a is relieved. The ability of PLN to regulate SERCA2a activity, thereby regulating the rate of cardiac relaxation and the size of the SR Ca 2ϩ store, makes PLN a crucial regulator of cardiac function (1, 2, 4, 5).SLN is a 31-aa SR membrane protein, which has no obvious phosphorylation site (6). Studies based on coexpression of PLN, SLN, and SERCA in heterologous cell culture show that PLN and SLN have similar ability to inhibit either SERCA1a or SERCA2a (7-9). PLN and SLN can form a binary complex that is superinhibitory, presumably because of the formation of a ternary PLN-SLN-SERCA2a complex (9, 10). Thus, SLN can regulate SERCA through either direct interaction with SERCA or through stabilization of the interaction between SERCA and PLN (10).SLN mRNA is expressed abundantly in human fast-twit...

We evaluated the effects of aging and hypertension on endothelium-dependent relaxation of rat common carotid arteries using 14-week-old (young) and 11-month-old (old) Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR). Isometric tension of common carotid artery ring segments was measured. With a resting tension of 2.0 g determined from the baseline tension-contraction curves, precontraction was induced by 10" and hypertension 13 -16 on vascular reactivity in general have been extensively studied. In addition, there are several reports examining the influence of aging or hypertension on endothelium-dependent vasodilatations. 17 -21 In these studies, ACh-induced relaxation of rat mesenteric artery was unaffected by age, 17 whereas hypertension impaired endothelium-dependent relaxation in experimental animals. 18 -21 There are at present, however, noFrom the Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, Virginia.Address for correspondence: Neal F. Kassell, MD, Department of Neurosurgery, Box 212, Medical Center, University of Virginia, Charlottesville, VA 22908.Received June 30, 1987; accepted February 3, 1988. reports of the effects of aging or hypertension on the endothelium-dependent relaxations of cephalic arteries. This is surprising considering the major effects that aging and hypertension are thought to exert on the cerebral circulation.Recently Freiman et al 22 demonstrated that atherosclerosis impairs endothelium-dependent vascular relaxation to ACh and thrombin in monkeys. The common carotid artery, which is often affected by disorders such as atherosclerosis, has a great influence on cerebral circulation. Therefore, it seems pertinent to investigate the effects of aging and hypertension on the endothelium-dependent vascular relaxation in a cephalic artery such as the common carotid artery. Our experiments were designed to demonstrate these effects using young and old Wistar-Kyoto rats (WKY) and young and old spontaneously hypertensive rats (SHR).

To investigate the feasibility of a newly developed, near-infrared optical spectroscopy device, we analysed measurements of the infrared tracer indocyanine green (ICG) using sensors with a single near infrared light source and multiple light detectors. Two ml of ICG dye, 1.0 mg ml-1 in concentration, were injected into the internal carotid artery during cerebral angiography in 14 adult patients. The resultant washout curves were measured bilaterally using sensors with 4 detectors spaced at 10, 20, 30 and 40 mm from the infrared light source on the right side, and 15, 25, 35 and 45 mm from the source for the left side, respectively. Washout curves were analysed to determine the relative amplitude of the ICG absorption signal and deduce each detector's penetration distance. When ICG was injected into the internal carotid artery, relative absorption increased with detector distance from the light source. No substantial difference in attenuation was observed in any of the detectors during external carotid injection of ICG. The resultant information related depth of penetration of the light with source-detector separation distances. The feasibility of the system for measuring cerebral oxygen saturation and haemodynamics noninvasively or monitoring at bedside is discussed.

Isolated rat ventricular myocytes were stretched using carbon fibres to investigate the mechanisms underlying the increase in contraction following stretch. 2. [Ca2+]i and [Na+]i were monitored using the fluorescent indicators fura‐2 and sodium‐binding benzofuran isophthalate, respectively. The L‐type Ca2+ current was recorded simultaneously with contraction using the perforated patch‐clamp technique. 3. Mechanical stretch caused an immediate increase in contraction, followed by a slow increase. Contraction was prolonged immediately after the stretch, but did not change during the slow phase. 4. The Ca2+ transient did not change immediately after the stretch. The slow increase in contraction was accompanied by an increase in the amplitude of the Ca2+ transient. However, diastolic [Ca2+]i did not change significantly following stretch. 5. [Na+]i did not change significantly either immediately, or during the slow increase in contraction, after the stretch. 6. The L‐type Ca2+ current was not significantly altered either by mechanical loading of the cell with carbon fibres or by stretching the cell. 7. These results suggest that: (1) the rapid increase in contraction following a stretch is due to an increase in myofilament Ca2+ sensitivity rather than to changes in the L‐type Ca2+ current or [Na+]i; and (2) a slow increase in the Ca2+ transient underlies the slow increase in contraction in isolated myocytes, but is not caused by either an increase in diastolic [Ca2+]i or a change in [Na+]i (and hence Ca2+ influx via Na(+)‐Ca2+ exchange) or a change in myofilament Ca2+ sensitivity.

The tumor growth rate of residual NFPAs is strongly influenced by the patient's age. The TVDT in elderly patients is much longer than that previously reported. Treatment strategies that take into consideration the natural history of residual adenomas should be established especially in the elderly population.

This review summarizes the presentation and outcome of a large series of 24 patients with 27 distal PICA aneurysms, and we conclude that distal PICA aneurysms are benign entities compared with vertebral artery-PICA aneurysms. Characteristics that should be considered in the treatment of distal PICA aneurysms are discussed.