Lerman, Lilach O.

Hypercholesterolemia induces renal inflammation and neovascularization, associated with renal endothelial dysfunction and injury. Neovascularization might conceivably represent a defense mechanism to sustain renal perfusion. Therefore, the present study was designed to test the hypothesis that preventing neovascularization using thalidomide, a potent anti-inflammatory and antiangiogenic agent, would impair basal renal hemodynamics in experimental hypercholesterolemia. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 weeks of hypercholesterolemia, hypercholesterolemia chronically supplemented with thalidomide (4 mg/kg per day), and normal controls. Renal microvascular architecture was then studied ex vivo using 3D microcomputed tomography imaging and inflammation, angiogenesis, and oxidative stress explored in renal tissue. The density of larger microvessels (200 to 500 μm) was selectively decreased in hypercholesterolemia plus thalidomide and accompanied by a decreased fraction of angiogenic, integrin β 3 -positive microvessels (9.9%±0.9% versus 25.5%±1.7%; P <0.05 versus hypercholesterolemia), implying decreased angiogenic activity. Furthermore, thalidomide increased renal expression of endothelial NO synthase and decreased tumor necrosis factor-α and renal inflammation but did not decrease oxidative stress. Thalidomide also decreased basal renal blood flow and glomerular filtration rate but normalized the blunted renal hemodynamic responses in hypercholesterolemia. Attenuated inflammation and pathological angiogenesis achieved in hypercholesterolemia by thalidomide are accompanied by restoration of renovascular endothelial function but decreased basal renal hemodynamics. This study, therefore, suggests that neovascularization in the hypercholesterolemic kidney is a compensatory mechanism that sustains basal renal vascular function.

Background— Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) is a novel marker and participant in vascular inflammation. Inflammation also is associated with coronary atherosclerosis. We tested the hypothesis that local coronary production of Lp-PLA 2 is enhanced in patients with early coronary atherosclerosis and associated with local endothelial function. Methods and Results— Coronary angiography, blood flow, flow reserve, endothelial function assessment, and intravascular ultrasound with volumetric analysis were performed in 15 patients with mild coronary atherosclerosis and in 15 control subjects. Plasma samples were collected simultaneously from the left main coronary artery and coronary sinus for measurement of Lp-PLA 2 , lysophosphatidylcholine (a product of Lp-PLA 2 ), and C-reactive protein. Hemodynamic parameters and cholesterol were similar in both groups. Arterial Lp-PLA 2 levels were similar in patients and control subjects: 225 ng/mL (interquartile range [IQR], 196 to 273 ng/mL) versus 221 ng/mL (IQR, 177 to 294 ng/mL). Lp-PLA 2 net production in the coronary circulation was higher in patients compared with control subjects: 519 ng/min (IQR, 198 to 1276 ng/min) versus −529 ng/min (IQR, −872 to −79 ng/min; P =0.001) and correlated with percent atheroma volume ( r s =0.37, P =0.04). Net production of lysophosphatidylcholine was higher in patients compared with control subjects: 199 ng/min (IQR, −592 to 470 ng/min) versus −505 ng/min (IQR, −1119 to 0 ng/min; P =0.03) and correlated with coronary endothelial dysfunction ( r s =0.5, P =0.005). C-reactive protein was not significantly different between the groups. Conclusions— Early coronary atherosclerosis in humans is characterized by local production of Lp-PLA 2 . Local coronary production of lysophosphatidylcholine, the active product of Lp-PLA 2 , is associated with endothelial dysfunction. These results support the role for Lp-PLA 2 in the mechanism of regional vascular inflammation and atherosclerosis in humans.

The discovery of the ubiquitin system was awarded with the Nobel Prize in Chemistry in 2004. Labeling of intracellular proteins for degradation by a multienzymatic complex, called the proteasome, was identified as the main function of this system. Subsequently, it was discovered that the attachment of ubiquitin to proteins can modify their function without degradation. Finally, a number of other molecules were recognized to be conjugated to proteins in a manner similar to ubiquitin and were henceforth called ubiquitin-like proteins. This review provides an overview of this class of molecules and its implication for function, subcellular location, and half-life of proteins.

Despite advances in imaging, understanding the underlying pathways, and clinical translation of animal models of disease there remains an urgent need for therapies that reduce brain damage after stroke and promote functional recovery in patients. Blocking oxidant radicals, reducing matrix metalloproteinase-induced neuronal damage, and use of stem cell therapy have been proposed and tested individually in prior studies. Here we provide a comprehensive integrative management approach to reducing damage and promoting recovery by combining biological therapies targeting these areas. In a rat model of transient cerebral ischemia (middle cerebral artery occlusion) gene delivery vectors were used to overexpress tissue inhibitor of matrix metalloproteinase 1 and 2 (TIMP1 and TIMP2) 3 days before ischemia. After occlusion, autologous bone marrow cells alone or in combination with agents to improve NO bioavailability were administered intraarterially. When infarct size, BrdU incorporation, and motor function recovery were determined in the treatment groups the largest beneficial effect was seen in rats receiving the triple combined therapy, surpassing effects of single or double therapies. Our study highlights the utility of combined drug, gene, and cell therapy in the treatment of stroke.

Moderate physical exercise (PE) combined with metabolic treatment (MT) (antioxidants and l -arginine) are well known to reduce atherosclerotic lesion formation in hypercholesterolemic mice. However, the long-term beneficial effects on unstable atheroma remain poorly understood. We started early PE training in large groups of 6-week-old hypercholesterolemic mice (by graduated swimming) alone or in combination with nutritional supplementation (1.0% vitamin E added to the chow and 0.05% vitamin C and 6% l -arginine added to the drinking water). Inactive controls did not receive PE. The spontaneous development of atherosclerotic plaque rupture (associated with advanced atherosclerosis) and survival rates were evaluated. Moderate PE elicited an increase in plasma levels of nitric oxide. Early combined treatment with PE and MT in the hypercholesterolemic mice significantly reduced lesions (also detected noninvasively at 10 months) and spontaneous atherosclerotic plaque rupture and prolonged survival more effectively than each intervention alone. Thus, early concerted actions of MT and PE improve the natural history of atherosclerotic lesions and reduce the plaque instability in hypercholesterolemic mice.

Atherogenesis is the pathobiological process, which underlies atherosclerotic cardiovascular disease and evolves in the 3 stages of initiation, progression, and complication to clinical significance. Of note, this process is associated with neovascularization, and it was not until recently that the implications of angiogenesis in atherogenesis were delineated. This article gives an updated overview on this topic and briefly reflects on the similarities with neovessel formation in carcinogenesis.

ABSTRACT We tested the hypothesis that statins would decrease renal injury in renal artery stenosis (RAS) by restoring angiogenesis and attenuating intrarenal microvascular (IMV) remodeling. Single‐kidney hemodynamics and function were quantified using electron‐beam‐computed tomography (CT) in normocho‐lesterolemic pigs after 12 wk of experimental RAS, RAS supplemented with simvastatin (RAS+simvastatin), and normal controls. Renal circulation was also studied in vivo using angiography and ex vivo using a unique 3D micro‐CT imaging technique. Angiogenic and remodeling pathways were subsequently explored in renal tissue. Blood pressure and the degree of stenosis were similarly increased in RAS groups. Simvastatin in RAS enhanced both intrarenal angiogenesis and peri‐stenosis arteriogenesis and increased the expression of angiogenic growth factors and hypoxia‐inducible factor‐1α. Furthermore, simvastatin decreased tissue‐transglutaminase expression and IMV inward remodeling, restored IMV endothelial function, decreased fibrogenic activity, and improved renal function. Chronic simvastatin supplementation promoted angiogenesis in vivo, decreased ischemia‐induced IMV remodeling, and improved IMV function in the stenotic kidney, independent of lipid lowering. These novel renoprotective effects suggest a role for simvastatin in preserving the ischemic kidney in chronic RAS.— Chade, A. R., Zhu, X., Mushin, O. P., Napoli, C., Lerman, A., Lerman, L. O. Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia. FASEB J. 20, E1014–E1023 (2006)