Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.
ABSTRACT. The aim of this collaborative study was to normalized by therapy, the levels of the catabolites of investigate whether guanidino compound analyses in the arginine are still elevated. (Pediatr Res 27: 297-303,1990) biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, a-keto-6-guanidinoDeficiency of arginase, the last enzyme of the urea cycle, leads valeric acid, argininic acid, and N-a-acetylarginine levels to hyperargininemia. The first clinical and biochemical descripof all the hyperargininemic patients are higher than the tions of two sisters affected with hyperargininemia were pubnormal range. Similar increases were seen for the urinary lished in 1969 (1) and 1970 (2, 3). Five y later, another sister was excretion of a-keto-6-guanidinovaleric acid and argininic diagnosed shortly after birth (4). Since then, 19 other cases from acid. Untreated hyperargininemic patients have the highest 17 families have been reported (5-22). Patients with hyperargiguanidino compound levels in cerebrospinal fluid. How-ninemia present a neuropsychiatric syndrome consisting of varyever, even under therapy, the arginine, homoarginine, a-ing degrees of mental retardation, epilepsy, and progressive spasketo-6-guanidinovaleric acid, and argininic acid levels in ticity. This latter symptom is at variance with other defects of cerebrospinal fluid are still increased. Protein restriction the urea cycle. Some patients have, in addition, recurrent epialone is not sufficient to normalize the hyperargininemia, sodes of vomiting and irritability accompanied by moderate but protein restriction together with supplementation of hyperammonemia. As a consequence of the arginase deficiency, essential amino acids with or without sodium benzoate the patients accumulate excessive arginine. Some secondary cadecreases further the arginine levels. However, whereas tabolites of arginine, guanidino compounds, are massively exthe argininemia can be normalized, the catabolites of ar-creted in the urine of these patients (23). Figure 1 shows some ginine are still increased. We conclude that the urinary proposed catabolic pathways of arginine in patients with hyperamino acid levels may remain normal in hyperargininemia, argininemia. whereas consistent increases of the guanidino compounds In hyperargininemia it is unclear whether ammonia is the are observed. Thus, guanidino compound analyses can be principal toxin. Indeed, the presence of normal or only slightly used as a complementary biochemical diagnostic parameter elevated ammonia levels has been demonstrated in several pafor hyperargininemia. Although the argininemia can be tients (6,7,9,15), and the progressive spasticity typically en-
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