Role Of Adiponectin In Protecting Against Cardiovascular Disease Biology Essay

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Exclusively secreted as of adipose tissue, (also known as GBP-28, apM1, AdipoQ and Acrp30) is a protein which is encoded by the ADIPOQ gene in humans. The size of the molecule is 30-KDa and it has 3 defined domains.(Scherer, Williams et al. 1995). Adiponectin was first characterized in mice as a transcript over expressed in preadipocytes (precursors of fat cells) differentiating into adipocytes. The N terminus contains a hyper variable region, which is commonly used as the antigenic site for species-specific antibody generation. The 30 kDa monomers of adiponectin has been demonstrated that to aggregate in different polymeric structures such as , human and mouse plasma, which involved hexameric and high-molecular weight oligomeric structures (Kishida, Nagaretani et al. 2003; Pajvani, Du et al. 2003). Additionally oligomers, adiponectin which might be as well procedure via proteolysis, in addition to a minor globular field fragment be able to be distinguished in plasma (Fruebis, Tsao et al. 2001). However, these a variety of structures of adiponectin are assumed to have different signaling that causes in the cardiovascular system (Lin, Kao et al. 2003; Pajvani, Du et al. 2003; Tsao and Yang 2003). However, the epidemiological studies on adiponectin have been showed that the role of adiponectin in obesity, diabetes and cardiovascular disease has been investigated during a number of epidemiological researches.

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The normal total plasma of adiponectin in human is a range from 3-30 μg/ml, (Arita, Kihara et al. 1999; Ouchi, Kihara et al. 2003). However, the levels of adiponectin are considerably reduced in obese people compared to non-obese human, such that a important negative correlation is found among body mass index (BMI) also plasma adiponectin levels (Arita, Kihara et al. 1999; Cnop, Havel et al. 2003) Adiponectin concentrationhas been unenthusiastically related with percent body fat and waistto-hip ratio(Cnop, Havel et al. 2003; Ryo, Nakamura et al. 2004) The main reason for that decrease in adiponectin in obese human still remains understood nevertheless it migh be due to either transcriptional inhibition or reduced secretion caused via inflammatory cytokines such as, pro-inflammatory cytokines (such as IL-6) are upregulated in the obese state and cause both a decrease in adiponectin mRNA and a reduction in adiponectin secretion from 3T3-L1 adipocytes (Fasshauer, Kralisch et al. 2003; Ouchi, Kihara et al. 2003).

Function:

Adiponectin is a protein hormone, produced into bloodstream utterly by adipocytes. It regulates the metabolism of glucose and lipids. The N terminus of the protein which is contained a hyper variable region; its most commonly utilized as an antigenic site for specific antibodies generations. It has been found abundantly in plasma while compared to other hormones. However, it is plays critical roles in suppressing the metabolic derangement, resulting to atherosclerosis, type 2 diabetes, and obesity. It is also create and secrete a quantity of other proteins (i.e. adipsin, properdin leptin, tumour necrosis factor (TNF) as well. It has played a vital key in metabolism of some carbohydrates such as glucose, in additation to vascular biology and energy homeostasis. An adipose tissue-specific factor was isolated and called as APM1 (AdiPose Most abundant gene transcript). The protein result of APM1 is adiponectin. When the adiponectin is secreted in the bloodstream it accounts approximately for 0.001% for all the plasma proteins then the sexual dimorphism is been revealed by the plasma concentrations. It has been found in higher levels in females than males. Furthermore, the levels of adiponectin are decreased in subject diabetics while compared to non-diabetics after that the weight reduction will considerably raise via circulating the levels. Additionally, the oligomers and adiponectin can also be procedured by different ways such as proteolysis, and a smaller globular domain fragment might be affected in plasma. However, these a range of structures of adiponectin are postulated to have distinct signalling defected in the cardiovascular system. The primary protein sequence of adiponectin contains a collagen-like domain at the N-terminus and a globular domain at the C terminus, similar to collagens VIII, X and complement factor C1q.

Receptors:

Adiponectin have two binds of receptors which have been identified as homology to G protein-coupled receptors and 1 receptor similar to cadherin family.

adiponectin receptor 1 - ADIPOR1

adiponectin receptor 2 - ADIPOR2

T-cadherin - T-Cad

These receptors have separate tissue specificities during the body, it's also have different affinities to the range of structures of adiponectin. These receptors have been found to affect the downstream target of AMP kinase, a significant cellular metabolic rate control point. Terms of the receptors are related with insulin levels, in addition to decrease in mouse models of diabetes, mainly in adipose tissue and skeletal muscle. Adiponectin receptor term has been increased via beta-cell exposure to the unsaturated free fatty acid oleate, in addition to treatment of insulin-producing cells with globular adiponectin induces lipoprotein lipase expression.

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Ten years after the discovery of adiponectin, the receptors have been identified. According to, Yamauchi et al a 30 isolated 2 related receptors structure human skeletal muscle via expression cloning. These receptors have been found to produces of distinct genes but share 67% sequence identity. AdipoR2 is specifically present in liver. Whiles, AdipoR1 is more ubiquitously expressed and enriched in muscle; however, adipoR1 and AdipoR2 in vitro and in vivo experiments have implicated both as significant mediators for adiponectin signaling. Adiponectin itself is organized in conditions of metabolic stress and via several hormones and factors included in regulation of metabolic function. The majority of factors with an important impact on adiponectin regulation have been inhibitory effects. These involved glucocorticoids catecholamines, cytokines (IL-6 and TNF-α), prolactin, growth hormone, and androgens. Cardiovascular disease is classified as diseases which include blood vessels and heat for example arteries and veins. There are a number of common cardiovascular diseases that involves aneurysm, stroke, Atherosclerosis, Myocardial infarction, and Cerebrovascular disease.

DISCUSSION

Adiponectin and Surrogates of Atherosclerosis

The levels of plasma adiponectin have been demonstrated to link to surrogate markers of atherosclerosis. Currently atherosclerosis has been believed as an inflammatory disease in addition to those at high risk of early atherosclerosis have high levels of circulating inflammatory markers such as CRP. The CRP independently can be lead to cardiovascular disease also is painstaking to be a biological mediator of atherosclerosis. However, in the humans male subjects, plasma adiponectin and CRP levels were negatively correlated (r = -0.29, P < 0.01). Decreased plasma adiponectin levels in women similarly showed positive association with CRP elevation. Therefore, adiponectin shows to play an anti-inflammatory role in atherogenesis.

Endothelial dysfunction is play the critical roles to cause for the atherogenesis, in addition to its clinical evaluation to be active as a biomarker for vascular disease.

Hypoadiponectinemia appears to be related with impaired endothelium-dependent vasorelaxation. In a study conduct on 202 hypertensive patients, it has been found that plasma adiponectin level was measured along with forearm blood flow by strain-gauge plethysmography. Plasma adiponectin level have been independently and greatly related with the vasodilator response to actions hyperemia (r = 0.257, P < 0.001), proposing that hypoadiponectinemia has linked with impaired endothelium-dependent vasorelaxation. Hormone regulated shows to be structure adipocytes sties of the adiponectine secretion. (Paul E. Szmitko et al, 2006)

While other study conducted on Japanese patients without a history of diabetes or cardiovascular disease, endothelial function is impaired in percentage to the severity of obesity, which was, in sequence, strongly associated to plasma adiponectin levels. Similarly, levels of plasma adiponectin were associated with impaired endothelium-dependent vasodilation independent of diabetes mellitus. Furthermore, Levels of adiponectin were related with direct measures of atheroma burden. Adiponectin has a strong connection to intima-media thickness between patients with coronary artery disease (P = 0.02).

In the Salzburg Atherosclerosis Prevention Program in subjects at high individual risk (SAPHIR) study, a study conducted on 1,515 middle-aged healthy white subjects, common carotid artery intima-media thickness (CIMT) and the presence of atherosclerotic plaques were measureed via B-mode ultrasound. After adjustment for established risk factors, for every 1 µg/ml decrease in adiponectin level, CIMT increased by 3.48 µm in men (95% CI, 1.23-5.73 µm) and by 2.39 µm in women (95% CI, 0.50-4.27 µm). Thus the negative organization of adiponectin levels and CIMT proposes hypoadiponectinemia was a risk factor for the increase of early atherosclerosis. The number of causes including in the regulation of metabolic function and adiponectine itself id controlled in conditions of metabolic stress. (Seung Hwan Han et al, 18th January 2007)

Adiponectin as a Molecular Regulator of Atherosclerosis

Adiponectin appeared to be as a biomarker for cardiovascular disease. As is the biologically active molecule seems to protect the lood vessels in each stage of atherogenesis. Atherosclerosis is mostly considered to be an inflammatory disease. There are two main stages, in the initial stages of altherogenesis includes endothelial dysfunction, resulting to low production or availability of NO and contracting factors, for instance angiotensin, endothelin-1 and oxidants. The NO is a key endothelium-derived relaxing factor which plays a critical key in the regulation of vasomotor function and vascular tone. As well as its vasodilatory effect. In addition to, NO is play as critical role to protects againstsuch as vascular injury, inflammation, and thrombosis via inhibiting leukocyte adhesion to the endothelium, maintaining vascular smooth muscle in a nonproliferative state, and limiting platelet aggregation.

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In return to the traditional cardiovascular risk factors, for example hypertension, hypercholesterolemia and diabetes, the endogenous defences of the vascular endothelium start to fail. The adiponectin obtains defensive activation in unlike obesity-associate diseases in addition to, it produces anti-inflammatory properties. (Yukihiro Takemura et al, 26th April 2007). For instance, oxidized LDL activates and changes the biological characteristics of the endothelium, partly, by raising the intracellular concentration of NO. Adiponectin possesses anti-inflammatory property, by shifting the level of NO at the level of the endothelium. It's induces NO construction in human aortic endothelial cells by creation of the AMPK pathway and superior endothelial NO synthase protein expression and mRNA. It is also contain super oxide generation and increase eNOS action in endothelial cells which are treating with oxidized LDL. Hence, via advance NO generation, adiponectin is provided to protect against the onset of endothelial dysfunction.

Previously endothelial dysfunction has been recognized; undergo inflammatory activation of endothelial cells have been characterized via raised expression of adhesion molecules. It is also Adhesion molecule expression has induced via proinflammatory cytokines (i.e. interleukin (IL)-1, IL-8, TNF-, in addition to the acute phase protein CRP. Once adherent to the adhesion molecules, the monocytes transmigrate into the tunica intima, passing between the endothelial cells, along a concentration gradient of monocyte chemo attractant protein-1. Within the arterial intima, the monocytes develop into macrophages and begin to express class A scavenger receptors (SR-As) that internalize modified lipoproteins, giving rise to lipid-laden macrophages or foam cells, which characterize early atherosclerotic lesions. Within the developing atheroma, the foam cells begin to secrete proinflammatory cytokines, maintaining the inflammatory milieu.

However, the role of adiponectin in the advance of cardiac disease still remains understood clear than it does for metabolic disorders. Some studies indicate that low adiponectin levels are associated with cardiovascular disease. For example, it has been shown that plasma adiponectin concentrations are lower in patients with clinical manifestations of coronary artery disease than in age- and BMI-adjusted control subjects independent of other risk factors. High plasma adiponectin levels are associated both with a lower risk of myocardial infarction in men and a moderately decreased risk for coronary heart disease in male diabetic patients. Adiponectin levels are also reported to rapidly decline following acute myocardial infarction. These studies suggest that hypoadiponectinemia is associated with the development of cardiovascular diseases that are prevalent in obese individuals. Circulating adiponectin levels are inversely correlated with other cardiovascular risk factors, including hyperlipidemia, high blood pressure and C-reactive protein (CRP) levels.

Finally, adiponectin levels may influence the development of chronic heart failure, but the epidemiological data are somewhat complex. This is due in part to the fact that while higher body mass indices are a risk factor for heart failure, obesity is a predictor of improved prognoses in patients with established chronic heart failure because wasting is strongly associated with the increased risk of death in the final stages of this disease In this regard, high adiponectin levels are a predictor of mortality in patients with heart failure Presumably, this paradoxical relationship exists because high body mass, hence low adiponectin, favors survival in end-stage heart failure. Therefore, studies should examine adiponectin levels in patients with stable heart failure.

Adiponectin and Hypertrophic cardiomyopathy

Currently, there are number of studies have been showed that adiponectin influences cardiac remodelling and functions to suppress pathological cardiac growth. In response to pressure overload caused by aortic constriction, APN-KO mice have enhanced concentric cardiac hypertrophy and increased mortality. Conversely, adenovirus-mediated delivery of adiponectin has been shown to attenuate cardiac hypertrophy in response to pressure overload in APN-KO, wild-type and diabetic db/db mice. APN-KO mice also exhibit increased cardiac hypertrophy in response to angiotensin II infusion, while adiponectin overexpression reduces the hypertrophy in this model (Shibata, Ouchi et al. 2004)

Adiponectin's actions in the setting of cardiac hypertrophy can be attributed to the modulation of intracellular growth signals in cardiac cells, including the AMPK signalling cascade While AMPK activity increases through phosphorylation as hearts undergo pressure overload hypertrophy (Tian, Musi et al. 2001). This increase in AMPK phosphorylation is attenuated in APN-KO mice (Shibata, Ouchi et al. 2004). Experiments in rat neonatal cardiac myocytes show that adiponectin activates AMPK, and inhibits the hypertrophic response to α-adrenergic receptor stimulation (Shibata, Ouchi et al. 2004). The inhibition of hypertrophic growth by adiponectin can be reversed by transduction with dominant-negative AMPK, providing further evidence that adiponectin acts through the AMPK signalling cascade. Activation of AMPK has been shown to inhibit protein synthesis in cardiac myocytes, which is mediated by a decrease in p70S6 kinase phosphorylation and an increase in phosphorylation of eukaryotic elongation factor-2 (Chan, Soltys et al. 2004). These anti-hypertrophic actions of adiponectin on AMPK are thought to occur via the AdipoR1 and R2 receptors (Fujioka, Kawabata et al. 2006). It has been seen that that both of these adiponectin receptors are expressed by cardiac myocytes and heart tissue (Yamauchi, Kamon et al. 2003)

Adiponectic and Vascular Remodelling

Additionally, adiponectin can also be modulated smooth muscle cell (SMC) growth in the advance and progression of vascular lesions In-vitro study has been indicated that adiponectin be able to suppress the proliferation of SMCs and reduces their directed migration to platelet-derived growth factor-BB(Arita, Kihara et al. 2002).

This study also has been demonstrated that adiponectin inhibits growth factor-stimulated extracellular signal-regulated kinase (ERK) signalling in human aortic SMC. While, other studies, adiponectin have been found to inhibit SMC proliferation throughout its ability to bind a variety of growth factors and interfere with their ability to activate receptor-mediated cellular responses(Wang, Lam et al. 2005) , consequently, adiponectin might impair growth signalling pathways in SMCs and prevent the proliferation of SMCs related with vascular lesions. These results of in vivo researchers have been dependable with this proposed inhibition of SMC growth via adiponectin. Such as, APN-KO mice exhibit increased neointimal hyperplasia and proliferation of SMCs following acute vascular injury conversely (Matsuda, Shimomura et al. 2002). Adenovirus-mediated adiponectin expression reduces the increase in neointimal thickening observed in APN-KO mice. The effects of adiponectin on smooth muscle cell proliferation propose that adiponectin might also function as an anti-atherogenic protein in the vasculature (Matsuda, Shimomura et al. 2002).

Adiponectin and Myocardial ischemia-reperfusion injury

The obesity-related disorder has a main impact on the occurrence of ischemic heart disease. It has been found that that adiponectin is cardio protective in this setting. Furthermore, Adiponectin reduces apoptosis in cardiac myocytes and fibroblasts which are depiction to hypoxia-reoxygenation stress. However, the transduction with dominant-negative AMPK blocks the pro-survival actions of adiponectin has been indicated that adiponectin reduces cardiac cell apoptosis during AMPK-dependent signalling. Likewise, current studies have been showed that following ischemia-reperfusion, APN-KO mice increase great infarcts than wild-type mice. These great infarcts have related with increased myocardial cell apoptosis and TNF-α expression in the APN-KO mice. Although, there are a number of researches have been indicated that cardiac AMPK activation is protective, it is significant to know that improved AMPK activity in the heart has been stated to increase recovery following ischemia reperfusion injury of ex vivo working hearts. These researches have been demonstrated that fatty acid oxidation and AMPK activity rates speedily increase within ischemia, resulting to cell death and intracellular acidosis. The role of adiponectin metabolic in the ex vivo operational heart was not evidently established, though the globular adiponectin has been shown to accelerate fatty acid oxidation independent of AMPK signalling. Moreover, further experiments have been required to explain the mechanism of adiponectin in the setting of ischemia/reperfusion injury and the putative role of AMPK in cardiac recovery.

Adiponectin and Obesity

In normally humans range the level of plasma adiponectin orginally range from 3-30 μg/ml. However, levels of adiponectin are considerably decreased in obese pateints compared to non-obese pateints, such that an important negative association was found among body mass index (BMI) and plasma adiponectin levels. Adiponectin concentration has been negatively related with percent body fat and intra-abdominal fat. Moreover, the reduction in adiponectin in obese patients still remains understood nevertheless it possibly due to either transcriptional suppression. Such as, pro-inflammatory cytokines for example, IL-6 are up regulated in the obese state and cause both a decrease in adiponectin mRNA and a reduction in adiponectin secretion from 3T3-L1 adipocytes.

Adiponectin and Type 2 diabetes

Recently studies have been stated that the role of adiponectin in Type 2 diabetes, a disease which is most to the obese individuals. Levels of Plasma adiponectin are lesser in patients with type 2 diabetes than in non diabetic controls between subjects with similar body mass indices (Hotta, Funahashi et al. 2000). On the other hand, people with great adiponectin concentrations show to be at a lower risk for developing type 2 diabetes (Lindsay, Funahashi et al. 2002). In conformity with these findings, there are other studies have been showed that rising adiponectin is a negative predictor of the advance of insulin resistance and type 2 diabetes in BMI-adjusted subjects populations(Snehalatha, Mukesh et al. 2003). Furthermore, several studies have been indicated that the patients suffering with the chronic coronary artery diseases have the low plasma adiponectin concentration compared to body mass index (BMI).one the other study has been stated that plasma adiponectin accumulates in the sub endothelial space of the vascular wall at an early stage of catheter injury and be able to be effected approximately macrophages in the injured human aorta at the site of a thrombus. The clarification in the some investigate propose that adiponectin accrues rapidly in the vascular wall when endothelial function is impaired and modulates the transformation of macrophages to foam cells in vivo.(Snehalatha, Mukesh et al. 2003)

Conclusion

Adiponectin has been showed that to act as an anti-inflammatory, cardio protective and insulin-sensitizing adipokine which shows to protect against such as, obesity-related metabolic disease. However, Pharmacological approaches have been found that enhance the molecular signaling of adiponectin structures the basis for future therapeutic interventions. Additional experimental researches have been showed that significance on the pathophysiological mechanisms of adiponectin and might grant required results for the prevention, treatment of obesity, and cardiovascular disease. However, adiponectin might contribute to the regulation of vascular homeostasis via its aptitude to affect a number of signaling pathways in the modulate excess inflammatory responses. Adiponectin serves as a regulator of cardiac injury throughout modulation of pro-survival reactions. There are numerous effects of adiponectin in the cardiovascular system related with the activation of and COX-2 and AMPK. The regulation of adiponectin in the progress of cardiac disease remains still known than metabolic disorders. Whereas a number of studies have been indicated that low adiponectin level is related with cardiovascular disease. Nevertheless not all studies are up to show such an association. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that might be significant for treating atherosclerosis and coronary heart disease. The current studies also have been stated that although adiponectin diseases incidence furthermore it is useful in protecting the cardiovascular diseases. Adiponectin is a key for future study in rising morbidity and mortality of cardiovascular disease. It is potential that recombinant adiponectin might have a useful therapeutic role in the treatment and prevention of cardiovascular diseases in many ways in the future.