Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pro-inflammatory factors such as the adipokine leptin and cytokine tumor necrosis factor-alpha (TNFalpha) have been implicated in the onset of myocardial dysfunction in ischemia-reperfusion injury, sepsis, heart failure, viral myocarditis and cardiac allograft rejection. Although circulating TNFalpha and leptin levels are both elevated under a variety of inflammatory conditions, it remains unknown whether TNFalpha and leptin depress cardiac contractile function independently or synergistically. We examined the effect of acute (30 min) and short-term (24h) exposure of TNFalpha, leptin or both on cardiac contractile function in adult rat ventricular myocytes. Contractile properties were evaluated using an Ionoptix Softedge system including peak shortening (PS), maximal velocity of shortening/relengthening (+/-L/t), time-to-PS (TPS) and time-to-90% relengthening (TR(90)). Both TNFalpha (0.5-500 pg/ml) and leptin (1-100 nm) exerted concentration-dependent inhibitions in PS and +/-L/t following a 30-min exposure. TNFalpha but not leptin prolonged TR(90). Interestingly, TNFalpha-induced depression of cell shortening was masked by leptin and vice versa. Following a 24-h incubation, both TNFalpha and leptin significantly inhibited PS and +/-L/t without affecting TPS and TR(90). There was no additive or synergistic response by the two pro-inflammatory factors. The nitric oxide synthase inhibitor l-NMMA abolished depression of myocyte shortening elicited by TNFalpha, leptin or both. In summary, this study demonstrated that the inhibitory effect on cardiac contraction by TNFalpha and leptin may mask each other and share a common mechanism(s), probably dependent on NO.
 ...
PMID:Interaction between tumor necrosis factor-alpha and leptin-induced inhibition of cardiac contractile function in isolated ventricular myocytes. 1629 37

Apelin is a recently discovered vasoactive peptide that has been demonstrated to be the endogenous ligand of the APJ receptor. It was named 'apelin' after APJ endogenous ligand. This G protein-coupled receptor (GPCR), originally identified by O'Dowd et al. in 1993, has a close identity with the angiotensin II type 1 (AT1) receptor, but does not bind angiotensin-II. Although apelin and APJ have been found to be ubiquitously expressed in peripheral tissues, particularly the heart and lungs, as well as various regions of the central nervous system, the physiologic actions of apelin remain largely unknown. Nevertheless, some cardiovascular functions of the apelin/APJ system have been described, such as endothelium-dependent vasodilatation, vasoconstriction by direct action on the smooth muscle and positive inotropism. Other reported physiologic actions of apelin include: (1) its role as endocrine adipokine; (2) contribution to fluid homeostasis and thirst regulation; (3) participation as coreceptor in the process of human immunodeficiency virus type 1 infection; and (4) regulation of immune response. The involvement of apelin/APJ in the pathophysiology of heart failure (HF) and its potential as a therapeutic target in this syndrome have also been proposed. In the course of HF progression, plasma levels of apelin are significantly increased in the early stages, decreasing progressively towards normal in the advanced stages of the disease. Given the increasing number of studies focusing on the apelin/APJ system, the goal of this paper was to make an up-to-date review of existing information on apelin and APJ, with particular focus on their cardiovascular actions and potential use as a therapeutic target in HF.
 ...
PMID:Apelin: a novel neurohumoral modulator of the cardiovascular system. Pathophysiologic importance and potential use as a therapeutic target. 1639 42

Beyond glycemic control, the thiazolidinediones (TZDs) provide numerous cardiovascular benefits. Clinical data support a role for the TZDs in lowering blood pressure, correcting dyslipidemia, improving vascular structure and function, decreasing inflammation, improving the adipokine profile, reducing systemic oxidative stress, and possibly in stabilizing coronary plaques that may be prone to rupture. Data from the first outcomes trial assessing a TZD in reducing cardiovascular morbidity and mortality have recently been reported. Results were promising, but not conclusive. Therefore, other large studies currently underway should provide greater insight into the role of the TZDs in modifying cardiovascular risk in patients with type 2 diabetes. Reported side effects of the TZDs include fluid retention, worsening of heart failure, and weight gain. Recent research is beginning to clarify the mechanisms associated with these potential side effects and may result in the expanded use of this drug class in patients with heart failure. Because of the unique mechanism of action of this drug class that addresses a fundamental pathophysiolgical phenomenon in type 2 diabetes, namely, improving insulin resistance, and the growing body of evidence supporting cardiovascular benefits, strong consideration should be given to utilizing the TZDs early in the clinical course of diabetes.
 ...
PMID:The cardiovascular effects of the thiazolidinediones: a review of the clinical data. 1782 58

The 16 kDa adipokine leptin has been shown to exert direct hypertrophic effects on cultured cardiomyocytes although its role as an endogenous contributor to postinfarction remodeling and heart failure has not been determined. We therefore investigated the effect of leptin receptor blockade in vivo on hemodynamic function and cardiac hypertrophy following coronary artery ligation (CAL). Cardiac function and biochemical parameters were measured in rats subjected to 7 or 28 days of left main CAL in the presence and absence of a leptin receptor antibody. Animals subjected to an identical treatment in which the artery was not tied served as sham-operated controls. CAL produced myocardial hypertrophy, which was most pronounced 28 days postinfarction as demonstrated by increases in both left ventricular weight-to-body weight ratio and atrial natriuretic peptide gene expression, both of which were abrogated by leptin receptor antagonism. Leptin receptor blockade also significantly improved left ventricular systolic function, attenuated the increased left ventricular end-diastolic pressure, and reduced the expression of genes associated with extracellular matrix remodeling 28 days following CAL. In conclusion, the ability of a leptin receptor-neutralizing antibody to improve cardiac function offers evidence that endogenous leptin contributes to cardiac hypertrophy following CAL. The possibility exists that targeting the myocardial leptin receptor represents a viable and novel approach toward attenuating postinfarction remodeling.
 ...
PMID:A neutralizing leptin receptor antibody mitigates hypertrophy and hemodynamic dysfunction in the postinfarcted rat heart. 1846 42

Interleukin-1beta (IL-1beta) is a potent negative inotrope implicated in the functional abnormalities of heart failure. Because the adipokine, leptin, protects against some of the cardiovascular effects of endotoxin, we hypothesized that leptin may modulate the cardiosuppressive effects of IL-1beta in isolated cardiomyocytes. Ventricular cardiac myocytes isolated from adult male Sprague Dawley rats were analyzed simultaneously for electrically stimulated contractility and calcium transients following 30 min exposure to IL-1beta (10 ng/ml) with or without 60 min pretreatment with leptin (25 ng/ml). IL-1beta decreased cell shortening, depressed maximal velocities of shortening and relengthening, and prolonged the time to 90% relaxation. The change in fura2-AM fluorescence ratio amplitude (Delta[Ca(2+)]) was significantly depressed and the time to return to baseline [Ca(2+)] was prolonged. The negative inotropic effects of IL-1beta were blocked by the neutral sphingomyelinase inhibitor Manumycin A (5 microM) or the ceramidase inhibitor N-oleoyl ethanolamine (1 microM). Prior exposure of myocytes to leptin blocked IL-1beta-induced cardiosuppression in conjunction with a blunting of IL-1beta stimulated ceramide accumulation. These data suggest that leptin may modulate IL-1beta signaling through the sphingolipid signaling pathway in cardiomyocytes.
 ...
PMID:Leptin modulates the negative inotropic effect of interleukin-1beta in cardiac myocytes. 1853 86

The causal relationship between obesity and cardiovascular disease is extensively acknowledged; however, the exact mechanisms linking obesity and heart failure remain unclear. Here, we investigated the influence of adipokines derived from primary adipocytes on glucose and fatty acid uptake and metabolism in isolated primary cardiomyocytes. Either co-culture of these cell types or incubation with adipocyte-conditioned medium significantly increased glucose uptake in cardiomyocytes. When streptozotocin-induced diabetic rats were used as a source of adipocytes, there was a lower ability to elicit glucose uptake in cardiomyocytes which corresponded with lower Akt and AMPK phosphorylation. The profile of glucose metabolism also differed with oxidation being favored upon co-culture with wild-type adipocytes whereas lactate production was strongly induced by adipocytes from diabetic rats. Examination of fatty acid uptake revealed that stimulation only occurred in response to adipokines secreted by wild-type rat adipocytes. Importantly, oxidation of fatty acids by cardiomyocytes was decreased by adipokines derived from diabetic rat adipocytes. Analysis of adipokine profiles in diabetic rat adipocyte-conditioned medium demonstrated the most significant decreases in adiponectin and leptin with increased IL6 expression. Taken together, these data suggest that the profile of adipokines secreted by adipocytes from diabetic rats have a deleterious influence on cardiomyocyte metabolism which may be of relevance in the pathophysiology of heart failure.
 ...
PMID:Differential impact of adipokines derived from primary adipocytes of wild-type versus streptozotocin-induced diabetic rats on glucose and fatty acid metabolism in cardiomyocytes. 1878 59

Owing to the increased incidence of obesity and its association with heart failure, there is now great interest in elucidating the underlying molecular mechanisms linking these pathologies. Since the discovery of adipose-derived hormones and cytokines, their important regulatory role in myocardial function has emerged. The events that these adipokines can regulate include alterations in myocardial metabolism, cardiomyocyte hypertrophy, cell death, and structure and composition of the extracellular matrix. Here, we focus on the last of these and review current research demonstrating an important role for adipokines, with particular emphasis on leptin and adiponectin, in regulating matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and collagens. From this, it is clear that adipokines are capable of contributing to remodeling of the myocardial extracellular matrix, and the altered adipokine profiles observed in obese individuals may be important in the pathogenesis of heart failure. The feasibility of adipokine manipulation as a potential therapeutic treatment in preventing maladaptive cardiac remodeling is also discussed.
 ...
PMID:Implications of myocardial matrix remodeling by adipokines in obesity-related heart failure. 1918 9

Adiponectin is an adipokine whose biosynthesis is deranged in obesity and diabetes mellitus, predisposing to atherosclerosis. Evidence suggests that adiponectin has anti-atherogenic properties by improving endothelial function and having anti-inflammatory effects in the vascular wall. In addition, adiponectin modifies vascular intracellular redox signalling and exerts indirect antioxidant effects on human myocardium. However, its clinical role in cardiovascular disease is obscure. Adiponectin's positive prognostic value in coronary artery disease had been widely supported over the last years, but this view has been questioned recently. High adiponectin levels are paradoxically associated with poorer prognosis in heart failure syndrome. These controversial findings seem surprising as adiponectin has been viewed overall as an anti-atherogenic molecule. Therefore, any certain conclusion about adiponectin's role in cardiovascular disease seems premature. Despite the rapidly accumulating literature on this adipokine, it is still unclear whether adiponectin is a key mediator or a bystander in cardiovascular disease. It is still uncertain whether adiponectin levels have any clinical significance for risk stratification in cardiovascular disease or they just reflect the activation of complex and opposing underlying mechanisms. Circulating adiponectin levels should be interpreted with caution, as they may have completely different prognostic value, depending on the underlying disease state.
 ...
PMID:Adiponectin: from obesity to cardiovascular disease. 1938 61

Adiponectin is an adipose tissue-derived adipokine abundant in human plasma. Increasing evidence from experimental studies suggests that adiponectin plays a protective role in the cardiovascular system. However, epidemiological studies revealed that high levels of adiponectin were associated with increased mortality and severity of congestive heart failure. Furthermore, several prospective studies indicated that high levels of adiponectin were positively correlated with increased total and cardiovascular disease mortality in the elderly. These results are completely opposite to our expectation based on the beneficial effects of adiponectin. Clinical observations demonstrated that plasma adiponectin levels were positively associated with B-type natriuretic peptide levels. Clinical and experimental studies indicated that the administration of atrial natriuretic peptide enhanced adiponectin production. It is still controversial whether increased adiponectin production is a bystander or a key mediator in the development of heart failure. However, recent investigations strongly suggest that increased adiponectin production in patients with heart failure is a part of compensatory mechanisms against oxidative stress and inflammation. In addition, complicated "adiponectin resistance" will accelerate a counter-regulatory increase in adiponectin in patients with advanced heart failure, although direct evidence that patients with heart failure have "adiponectin resistance" is still lacking. Increased adiponectin production might contribute, at least in part, to the metabolic and structural remodeling of the failing heart via activation of AMP-activated protein kinase and induction of cyclooxygenase-2. Further investigation is needed to clarify the exact role of increased adiponectin production under pathophysiological conditions.
 ...
PMID:Is adiponectin a bystander or a mediator in heart failure? The tangled thread of a good-natured adipokine in aging and cardiovascular disease. 2020 4

Although increasing evidence indicates that an adipokine adiponectin exerts protective actions on heart, its effects on coronary angiogenesis following pressure overload have not been examined previously. Because disruption of angiogenesis during heart growth leads to contractile dysfunction and heart failure, we hypothesized that adiponectin modulates cardiac remodeling in response to pressure overload through its ability to regulate adaptive angiogenesis. Adiponectin-knockout (APN-KO) and wild-type (WT) mice were subjected to pressure overload caused by transverse aortic constriction (TAC). APN-KO mice exhibited greater cardiac hypertrophy, pulmonary congestion, left ventricular (LV) interstitial fibrosis and LV systolic dysfunction after TAC surgery compared with WT mice. APN-KO mice also displayed reduced capillary density in the myocardium after TAC, which was accompanied by a significant decrease in expression of vascular endothelial growth factor (VEGF) and phosphorylation of AMP-activated protein kinase (AMPK). Inhibition of AMPK in WT mice resulted in aggravated LV systolic function, attenuated myocardial capillary density and decreased VEGF expression in response to TAC. The adverse effects of AMPK inhibition on cardiac function and angiogenic response following TAC were diminished in APN-KO mice relative to WT mice. Moreover, adenovirus-mediated VEGF delivery reversed the TAC-induced deficiencies in cardiac microvessel formation and ventricular function observed in the APN-KO mice. In cultured cardiac myocytes, adiponectin treatment stimulated VEGF production, which was inhibited by inactivation of AMPK signaling pathway. Collectively, these data show that adiponectin deficiency can accelerate the transition from cardiac hypertrophy to heart failure during pressure overload through disruption of AMPK-dependent angiogenic regulatory axis.
 ...
PMID:Adiponectin deficiency exacerbates cardiac dysfunction following pressure overload through disruption of an AMPK-dependent angiogenic response. 2020 34


1 2 3 4 5 6 Next >>