Obesity is a risk factor for cardiovascular disease. C1q/tumor necrosis factor-related protein 9 (CTRP9) is an adipokine that is downregulated by obesity. We investigated the role of CTRP9 in cardiac injury with loss-of-function genetic manipulations and defined the receptor-mediated signaling pathway downstream of this adipokine. CTRP9-knockout (CTRP9-KO) mice at the age of 12 weeks were indistinguishable from wild-type (WT) mice under basal conditions. CTRP9-KO mice had exacerbated contractile left ventricle dysfunction following intraperitoneal injection of lipopolysaccharide (LPS) compared to WT mice. Administration of LPS to CTRP9-KO mice also resulted in increased expression of proinflammatory cytokines and oxidative stress markers in the heart compared to WT mice. Likewise, CTRP9-KO mice showed increased myocardial infarct size and elevated expression of inflammatory mediators in ischemic heart following ischemia and reperfusion compared to WT mice. Treatment of cardiac myocytes with CTRP9 protein led to suppression of LPS-induced expression of proinflammatory genes, which was reversed by blockade of AMPK or ablation of adiponectin receptor I (AdipoR1). Systemic delivery of CTRP9 attenuated LPS-induced cardiac dysfunction in WT mice but not in muscle-specific transgenic mice expressing dominant-negative mutant form of AMPK or in AdipoR1-knockout mice. CTRP9 protects against acute cardiac damage in response to pathological stimuli by suppressing inflammatory reactions through AdipoR1/ AMPK-dependent mechanisms.O besity causes the progression of various cardiovascular disorders, including ischemic heart disease (1, 2). Adipose tissue functions as an endocrine organ by producing various bioactive secreted proteins, also known as adipokines, that can directly affect the nearby or remote tissues (3). Most adipokines promote obese complications with proinflammatory properties. In contrast, a few numbers of adipokines such as adiponectin are downregulated in obese states, and these factors typically exert salutary actions on obesity-linked cardiovascular disorders (3, 4).C1q/tumor necrosis factor-related protein families (CTRPs) are conserved paralogs of adiponectin that contain collagen-like and globular C1q-like domains (5). CTRP9 has the highest amino acid identity to adiponectin among CTRPs (6). Like adiponectin, CTRP9 is abundantly expressed in adipose tissue. Plasma CTRP9 levels are reduced in diet-induced or leptin-deficient obese mice (6). Clinically, CTRP9 levels associate negatively with visceral fat adiposity and positively with favorable glucose or metabolic phenotypes (7).Several experimental studies demonstrated that CTRP9 acts as an adipokine that modulates metabolic and cardiovascular function. Systemic delivery of CTRP9 lowers glucose levels in obese mice (6). Transgenic overexpression of CTRP9 is protective against diet-induced obesity and glucose intolerance (8), whereas CTRP9-deficiency exacerbates insulin resistance and hepatic steatosis (9). These results suggest that CTRP9 plays a physiolo...

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Our findings indicate that muscle-derived Fstl1 attenuates neointimal formation in response to arterial injury by suppressing SMC proliferation through an AMPK-dependent mechanism. Thus, the release of protein factors from muscle, such as Fstl1, may partly explain why the maintenance of muscle function can have a therapeutic effect on the cardiovascular system.

These data document for the first time that omentin reduces the development of atherosclerosis by reducing inflammatory response of macrophages through the Akt-dependent mechanisms.

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.

Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-a and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-a-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.

Cold labiUlty of pyruvate, orthopbosphate dikinase was investigated using a homogeneous, purified enzyme preparation from maize (Zea mays L. var. Golden Cross Bantam T51) leaves. Its stability was markedly reduced below about 10 C and the rate of cold inactivation folowed first order kinetics at a concentration lower than about 0.1 miligram of enzyme per milliliter. Cold inactivation was little affected by pH in the range which gives good stabilty for the enzyme at warm temperatures and the enzyme activity was protected strongly by inclusion of substrates (pyruvate and phosphoenolpyruvate) and polyols such as sucrose, sorbitol, and glycerol.Loss of catalytic activity was accompanied by an apparent dissociation of a tetrameric form of the enzyme (9S form) into a new, more slowly sedimenting (5.1S) component. Inclusion of pyruvate at 4 mM in the coldtreated enzyme had no effect on the sedimentation value. A sharp change in activation energy of the dkinase-catalyzed reaction was observed near 12 C and its break point appears to be close to the generally accepted critical low temperature Himit for the growth of maize plants.An unusual inactivation by cold temperatures of pyruvate, Pi dikinase (EC 2.7.9.1) from C4 plants has received considerable attention since the initial report by Hatch and Slack (1). The property of cold lability of the dikinase was confirmed and its reversibility was established in our laboratory using the enzyme from maize leaf purified to homogeneity (11). Our previous data indicated a possible correlation between the cold response of this enzyme and thermal response in maize cultivars (12). Such a correlation supports the view that the enzyme may be a ratelimiting step in photosynthesis in C4 plants at cool temperature, as has been mentioned by Taylor et al. (13).In this paper we investigated the property of cold lability of the maize leaf dikinase and discuss its relation to photosynthetic CO2 fixation at low temperature. This is an attempt to describe more fully the cold-labile nature of the enzyme in view of its possible physiological meaning. MATERIALS AND METHODS PLANT MATERIALSMaize plants (Zea mays L. var. Golden Cross Bantam T5 1) were grown for 2 to 5 weeks in a greenhouse under natural light conditions at 15 to 35 C.

Background: Tissue ischemia stimulates production of secreted factors that regulate angiogenesis. Results: Neuron-derived neurotrophic factor (NDNF) is up-regulated in endothelial cells in ischemic limbs of mice. NDNF stimulates endothelial cell function and promotes ischemia-induced revascularization through NOS-dependent mechanisms. Conclusion: NDNF functions as a novel modulator that stimulates revascularization processes. Significance: NDNF represents a novel therapeutic target for ischemic vascular diseases.