Injury of the arterial wall induces the formation of the neointima. This structure is generated by the growth of mitogenically activated smooth muscle cells of the arterial wall. The molecular mechanism underlying the formation of the neointima involves deregulated cell growth, primarily triggered by the injury of the arterial wall. The activated gene products transmitting the injury-induced mitogenic stimuli have been identified and inhibited by several means: transdominant negative expression vectors, antisense oligodeoxynucleotides, adenovirus-mediated gene transfer, antibodies and inactivating drugs. Results of our study show that local administration of 3',5'-cyclic AMP and phosphodiesterase-inhibitor drugs (aminophylline and amrinone) to rats markedly inhibits neointima formation after balloon injury in vivo and in smooth muscle cells in vitro. The growth inhibitory effect of aminophylline was completely reversed by the inhibition of cAMP-dependent protein kinase A (PKA). These findings indicate an alternative approach to the treatment of diseases associated with injury-induced cell growth of the arterial wall, as stimulation of cAMP signaling is pharmacologically feasible in the clinical setting.
In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.
OBJECTIVETo evaluate whether the high triglyceride-to-HDL cholesterol (TG-to-HDL-C) ratio is associated with cardiometabolic risk (CMR) factors and preclinical signs of organ damage in an outpatient population of white children and adolescents.RESEARCH DESIGN AND METHODSThe study population included 884 subjects (aged 6–16 years), of whom 206 (23%) were normal weight, 135 (15%) were overweight, and 543 (61%) were obese. Biochemical variables were analyzed in the whole sample, whereas homocysteine and left ventricular (LV) geometry and function were evaluated in 536 and 258 children, respectively.RESULTSThe percentage of pubertal children (P < 0.001), as well as measurements of BMI, waist circumference, homeostasis model assessment of insulin resistance, white blood cell count, alanine aminotransferase (ALT), systolic blood pressure (P < 0.0001, for all), creatinine (P < 0.001), and diastolic blood pressure (P < 0.02), increased from the lowest to the highest tertile of the TG-to-HDL-C ratio. Age, sex, homocysteine, and glomerular filtration rate did not change. Moreover, interventricular septum thickness, relative wall thickness, and LV mass index (P = 0.01 to P < 0.0001) increased across tertiles of the TG-to-HDL-C ratio. Children with a TG-to-HDL-C ratio ≥2.0 showed a two- to threefold higher risk of elevated ALT levels and concentric LV hypertrophy than those with a TG-to-HDL-C ratio <2.0, independent of confounding factors.CONCLUSIONSThe high TG-to-HDL-C ratio is associated with several CMR factors and preclinical signs of liver and cardiac abnormalities in the outpatient, white pediatric population. Thus, a TG-to-HDL-C ratio ≥2.0 may be useful in clinical practice to detect children with a worsened CMR profile who need monitoring to prevent cardiovascular disease in adulthood.
Background-Patients with cardiac hypertrophy are at increased cardiovascular risk. It has been hypothesized that hydroxymethylglutaryl coenzyme A reductase inhibitors may exert beneficial effects other than their cholesterollowering actions. The aims of the study were to assess the in vivo effects of simvastatin (SIM) on cardiac hypertrophy and on Ras signaling in rats with ascending aorta banding. Methods and Results-Wistar rats were randomized to receive either treatment with SIM or placebo, and then short-term (group I) and long-term (group II) left ventricular pressure overload was performed by placing a tantalum clip on ascending aorta. At the end of treatment period, left and right ventricular weight, body weight, and tibial length were measured and echocardiographic evaluations were performed. Ras signaling was investigated by analyzing Ras membrane localization and activation, ERK2 phosphorylation, and p27 kip1 and cdk4 levels. In SIM-treated rats, a significant reduction of left ventricular weight/body weight, echocardiographic left ventricular mass, and left ventricular end-diastolic diameter and end-diastolic pressure was found. In rats with pressure overload, SIM treatment significantly reduced Ras membrane targeting, Ras in vivo activation, ERK2 phosphorylation, and the ratio cdk4/p27 kip1 . Conclusions-HMG CoA inhibitor SIM inhibits in vivo Ras signaling and prevents left ventricular hypertrophy development in aortic-banded animals.
An early stage of diabetic cardiomyopathy can be evidenced by TDI in Type 2 diabetic subjects even in the presence of a normal cardiac function with CE. This abnormality is associated with insulin resistance.
The best animal angioplasty model is the porcine model, which is expensive and not available in all laboratories. The aim of this study was to describe a new rat model of angioplasty. An injury was induced with the use of a standard percutaneous transluminal coronary angioplasty (PTCA) 1.5-mm balloon catheter. The neointimal tissue, arterial dimensions, and the injury index were assessed following angioplasty. Ki-67 expression was detected to evaluate cell turnover after balloon angioplasty. In contrast with the standard Clowes model, a significant neointimal formation was detected only in the presence of ruptured internal elastic lamina (IEL). A positive correlation between the percentage of ruptured IEL and the amount of neointimal tissue was also demonstrated. The percentage of IEL fracture correlates with the proliferation index by anti-Ki-67 immunolabeling 7 and 14 days after the angioplasty. Significant arterial negative remodeling was observed following PTCA balloon dilation. In conclusion, our inexpensive animal model of restenosis after angioplasty may have great relevance toward a better understanding of the mechanisms and toward assessment of new therapeutical strategies for this phenomenon.
Abstract-cAMP-dependent protein kinase is anchored to discrete cellular compartments by a family of proteins, the A-kinase anchor proteins (AKAPs). We have investigated in vivo and in vitro the biological effects of the expression of a prototypic member of the family, AKAP75, on smooth muscle cells. In vitro expression of AKAP75 in smooth muscle cells stimulated cAMP-induced transcription, increased the levels of the cyclin-dependent kinase-2 inhibitor p27 kip1 , and reduced cell proliferation. In vivo expression of exogenous AKAP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27 kip1 and inhibited neointimal hyperplasia. Both the effects in smooth muscle cells in vitro and in carotid arteries in vivo were specifically dependent on the amplification of cAMP-dependent protein kinase (PKA) signals by membrane-bound PKA, as indicated by selective loss of the AKAP75 biological effects in mutants defective in the PKA anchor domain or by suppression of AKAP effects by the PKA-specific protein kinase inhibitor. These data indicate that AKAP proteins selectively amplify cAMP-PKA signaling in vitro and in vivo and suggest a possible target for the inhibition of the neointimal hyperplasia after vascular injury. (Circ Res. 2001;88:319-324.) Key Words: A-kinase anchor proteins Ⅲ p27 Ⅲ protein kinase A Ⅲ smooth muscle cells C yclic AMP controls growth and differentiation in a variety of organisms and cell types. 1,2 In eukaryotes, cAMP binds the regulatory subunit of cAMP-dependent protein kinases (PKAs). This releases the catalytic subunit (C-PKA), which phosphorylates a wide variety of substrate proteins. A fraction of the C-PKA migrates to the nucleus and phosphorylates nuclear proteins and transacting factors. 3 PKA is targeted to certain subcellular locations by specific anchor proteins (A-kinase anchor proteins, AKAPs). Localized PKA holoenzymes might in vivo perform important aspects of cAMP-activated signal transduction. We have previously provided evidence that links membrane targeting of PKAII to cAMP-dependent gene transcription in differentiated and nondifferentiated cells. 4,5 In thyroid, neuronal, and kidney cells, displacement of immobilized PKAII from perinuclear sites to the cytoplasm impaired cAMP-induced transcription. 4 Conversely, overexpression of AKAP75, a prototype AKAP that targets PKA to the membranes, enhanced the propagation of cAMP signals to the nucleus. 5 However, the biological effects of AKAPs on smooth muscle cell (SMC) growth in vitro and in vivo are not known.Therefore, we performed 2 experimental models to assess the effects of AKAP expression on SMC proliferation both in vitro and in vivo. In the first model, we have transfected stabilized SMCs derived from aorta with expression vectors encoding the prototypic member of AKAP family, AKAP75 and its derivatives. The same vectors were also used in vivo in the rat model of angioplasty. After balloon injury, the cells in the media of the arterial wall are potently stimulated and proliferate v...
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