Clinical Impacts of Urinary Neutrophil Gelatinase-Associated Lipocalin in Patients With Chronic Kidney Disease Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor prognosis in patients undergoing percutaneous coronary intervention (PCI). Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker for renal injury. However, the association between urinary NGAL concentrations and renal and cardiovascular events in patients with CKD undergoing PCI has not been elucidated. This study investigated the clinical impact of urinary NGAL concentrations on renal and cardiovascular outcomes in patients with non-dialysis CKD undergoing PCI. METHODS AND RESULTS: We enrolled 124 patients with non-dialysis CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2) undergoing elective PCI. Patients were divided into low and high NGAL groups based on the median urinary NGAL concentration measured the day before PCI. Patients were monitored for renal and cardiovascular events during the 2-year follow-up period. Kaplan-Meier analyses showed that the incidence of renal and cardiovascular events was higher in the high than low NGAL group (log-rank P<0.001 and P=0.032, respectively). Multivariate Cox proportional hazards analyses revealed that urinary NGAL was an independent risk factor for renal (hazard ratio [HR] 4.790; 95% confidence interval [CI] 1.537-14.924; P=0.007) and cardiovascular (HR 2.938; 95% CI 1.034-8.347; P=0.043) events. CONCLUSIONS: Urinary NGAL could be a novel and informative biomarker for predicting subsequent renal and cardiovascular events in patients with CKD undergoing elective PCI.

Clinical features, future cardiac events, and prognostic factors following percutaneous coronary intervention in young female patients.

BACKGROUND: The proportion of young females among the patients who undergo percutaneous coronary intervention (PCI) is relatively small, and information on their clinical characteristics is limited. This study investigated the clinical characteristics and prognostic factors for future cardiac events in young females who underwent PCI. METHODS: This multicenter observational study included 187 consecutive female patients aged < 60 years who underwent PCI in seven hospitals. The primary composite endpoint was the incidence of cardiac death, nonfatal myocardial infarction, and target vessel revascularization. RESULTS: The mean patient age was 52.1 ± 6.1 years and 89 (47.6%) had diabetes, and renal dysfunction (an estimated glomerular filtration rate < 60 mL/min/1.73 m2) was observed in 38 (20.3%). During a median follow-up of 3.3 years, the primary endpoint occurred in 28 patients. The Cox proportional hazards models showed that renal dysfunction was an independent predictor for the primary endpoint (hazard ratio 3.04, 95% confidence interval 1.25-7.40, p = 0.01), as well as multivessel disease (hazard ratio 2.79, 95% confidence interval 1.12-6.93, p = 0.03). Patients with renal dysfunction had a significantly higher risk for the primary endpoint than those without renal dysfunction. CONCLUSIONS: Renal dysfunction was strongly associated with future cardiac events in young females who underwent PCI.

Prognostic impact of polypharmacy and discharge medications in octogenarians and nonagenarian patients with acute heart failure.

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF.

Long-term outcomes of percutaneous revascularization for internal mammary artery-left anterior descending artery bypass failure.

Despite the excellent long-term results of internal mammary artery (IMA)-left anterior descending (LAD) bypass, percutaneous revascularization of IMA is sometimes required for IMA-LAD bypass failure. However, its clinical outcomes have not been fully elucidated. The aim of this study was to investigate the long-term clinical outcomes, including target lesion revascularization (TLR) following contemporary percutaneous revascularization of failed IMA bypass graft. We examined data of 59 patients who had undergone percutaneous revascularization of IMA due to IMA-LAD bypass failure at nine hospitals. Patients with IMA graft used for Y-composite graft or sequential bypass graft were excluded. The incidence of TLR was primarily examined, whereas other clinical outcomes including cardiac death, myocardial infarction, and target vessel revascularization were also evaluated. Mean age of the enrolled patients was 67.4 ± 11.3 years, and 74.6% were men. Forty patients (67.8%) had anastomotic lesions, and 17 (28.8%) underwent revascularization within three months after bypass surgery. Procedural success was achieved in 55 (93.2%) patients. Stent implantation was performed in 13 patients (22.0%). During a median follow-up of 1401 days (interquartile range, 282-2521 days), TLR was required in six patients (8.5% at 1, 3, and 5 years). Patients who underwent percutaneous revascularization within 3 months after surgery tended to have a higher incidence of TLR. Clinical outcomes of IMA revascularization for IMA-LAD bypass failure were acceptable.

Improved Renal Function After Percutaneous Coronary Intervention in Non-Dialysis Patients With Acute Coronary Syndrome and Advanced Renal Dysfunction.

BACKGROUND: The deterioration of renal function is a strong prognostic predictor in patients with coronary artery disease. Although percutaneous coronary intervention (PCI) has sometimes resulted in improved renal function (IRF) in acute coronary syndrome (ACS) patients, its clinical implications have not been fully elucidated. This study aimed to investigate the prevalence and predictors of IRF after PCI and its relationship with long-term renal outcomes. METHODS: In this retrospective observational cohort study, we examined data from 177 ACS patients with non-dialysis advanced renal dysfunction (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m2) who underwent PCI. Patients with and without IRF were compared in terms of baseline demographic, clinical, and procedural characteristics and renal outcomes. IRF was defined as a 20% increase in eGFR from baseline at 7 or 30 days after the index PCI. RESULTS: IRF was observed in 66 (37.3%) patients. ST-elevation myocardial infarction and shock during PCI were independent predictors of IRF. Patients were followed up for a median of 695 days. Kaplan-Meier analyses demonstrated that patients with IRF had the lower incidence of initiation of permanent dialysis than those without IRF (Log-rank P = 0.015). CONCLUSIONS: IRF was relatively common in non-dialysis patients with ACS and advanced renal dysfunction who underwent PCI. ST-elevation myocardial infarction and shock, which may be indicative of hemodynamic instability during PCI, were independent predictors of IRF. Further, IRF was associated with favorable renal outcomes. Hemodynamic stabilization may be important for improving the short-term and long-term renal outcomes of high-risk patients.

Clinical characteristics and treatment of Spontaneous Coronary Artery Dissection in Young Women Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) has recently been recognized as a cause of acute coronary syndrome (ACS), especially in young women. However, the characteristics, optimal treatment, and prognosis of patients who experience SCAD have not been fully described. METHODS: Data were retrospectively collected from a multicenter registry. Among 187 young women less than 60 years of age who underwent percutaneous coronary intervention, 19 (10.2%) with SCAD were identified through coronary angiography. Clinical characteristics and outcomes were investigated. RESULTS: Those with SCAD less frequently exhibited coronary risk factors, such as diabetes, dyslipidemia, and smoking, than those without SCAD. Intense emotional and/or physical stress was more frequently observed as a prominent precipitating factor in cases of SCAD. All 19 SCAD patients presented with ACS, 7 of whom were treated using stents, and the other 12 treated without stents. During a median follow-up of 960 days (interquartile range, 686-1504 days), two recurrent coronary artery dissections occurred within 7 days, both of which occurred in a vessel other than that in which primary dissection occurred. There were no deaths or recurrent dissection after 1 week. CONCLUSION: SCAD was not uncommon among young Japanese women requiring percutaneous coronary intervention. Patients with SCAD exhibited fewer coronary risk factors and more precipitating factors than those without SCAD, and long-term clinical outcomes after an early period appeared to be favorable.

Long-term renal outcomes after elective percutaneous coronary intervention in patients with advanced renal dysfunction.

The aim of the present study was to evaluate the renal outcomes, including the time course of renal function, after elective PCI in patients with advanced renal dysfunction and to assess the predictors of renal dysfunction progression. This is a subanalysis of a previous observational multicenter study that investigated long-term clinical outcomes in patients with advanced renal dysfunction (eGFR < 30 mL/min/1.73 m2), focusing on 151 patients who underwent elective PCI and their long-term renal outcomes. Renal dysfunction progression was defined as a 20% relative decrease in eGFR at 1 year from baseline or the initiation of permanent dialysis within 1 year. Progression of renal dysfunction at 1 year occurred in 42 patients (34.1%). Among patients with renal dysfunction progression, the decrease of renal function from baseline was not observed at 1 month but after 6 months of the index PCI. Baseline eGFR and serum albumin level were significant predictors of renal dysfunction progression at 1 year. Among 111 patients who had not been initiated on dialysis within 1 year, those with renal dysfunction progression had a significantly higher incidence of dialysis initiation more than 1 year after the index PCI than those with preserved renal function (p < 0.001). Among patients with advanced renal dysfunction who underwent elective PCI, 34.1% showed renal dysfunction progression at 1 year. The decrease in renal function was not observed at 1 month but after 6 months of the index PCI in patients with renal dysfunction progression. Furthermore, patients with renal dysfunction progression had poorer long-term renal outcomes.

Clinical outcomes after percutaneous coronary intervention in non-dialysis patients with acute coronary syndrome and advanced renal dysfunction.

BACKGROUND: Data about the clinical outcomes of ACS patients with advanced renal dysfunction (estimated glomerular filtration rate < 30 mL/min/1.73 m2) following percutaneous coronary intervention (PCI) are limited. METHODS: We examined the data obtained from 194 ACS patients with non-dialysis advanced renal dysfunction who underwent PCI at five hospitals. The primary composite endpoint was the incidence of major adverse cardiac and cerebrovascular events (MACCE: all-cause death, myocardial infarction, and ischemic stroke). RESULTS: Eighty patients (41.2%) were diagnosed with ST-elevation myocardial infarction (STEMI), and 117 patients (58.8%) with non-ST-elevation ACS (NSTE-ACS). Overall patients were followed for a median of 657.5 days. Cumulative incidence of MACCE at median follow-up was 32.3% (45.4% for STEMI and 23.4% for NSTE-ACS). Kaplan-Meier analysis demonstrated that patients in the STEMI group had significantly higher incidence of MACCE than those in the non-STEMI and unstable angina group (Log-rank p < 0.001). In-hospital MACCE rate was higher in the STEMI group than in the NSTE-ACS group, whereas post-discharge MACCE rate was comparable between the two groups. In the multivariate analysis, STEMI and Killip classification ≥ 2 were associated with in-hospital MACCE. On the other hand, body mass index and serum albumin at admission were independent predictors of post-discharge MACCE. CONCLUSIONS: Short- and long-term prognoses following PCI in non-dialysis patients with ACS and advanced renal dysfunction is still unfavorable. STEMI and Killip classification ≥ 2 were independent predictors for in-hospital MACCE, and body mass index and serum albumin were for post-discharge MACCE.

Contrast-Induced Nephropathy and Long-Term Clinical Outcomes Following Percutaneous Coronary Intervention in Patients With Advanced Renal Dysfunction (Estimated Glomerular Filtration Rate <30 ml/min/1.73 m2).

The incidence of contrast-induced nephropathy (CIN) increases with the progression of renal dysfunction. Recent reports have shown that percutaneous coronary intervention (PCI) can be safely performed even in patients with advanced renal dysfunction by appropriate CIN-prevention strategies. However, data are limited regarding the occurrence and prognostic influence of CIN in patients with advanced renal dysfunction. We examined the data obtained from 323 consecutive patients with advanced renal dysfunction (eGFR <30 ml/min/1.73 m2) who underwent PCI at 5 hospitals. CIN was defined as a ≥25% increase in baseline serum creatinine levels and/or a ≥0.5 mg/dl increase in absolute serum creatinine levels within 72 hours after PCI. Incidence of all-cause death and the initiation of permanent dialysis were examined during follow-up. The prevalence of emergency/urgent PCI was 53.3%. Intravascular ultrasound was used in 266 patients (82.4%), and the volume of contrast used was 71.7 ± 57.2 ml. CIN was observed in 31 patients (9.7%). The median follow-up duration was 656 days (interquartile range 257-1143 days). The cumulative rates of all-cause death or the initiation of permanent dialysis, all-cause death, and the initiation of permanent dialysis were 38.1%, 25.9%, and 18.2%, respectively, at 2 years. A comparison between patients with and without CIN showed no significant intergroup differences in the occurrence of the aforementioned events. In conclusion, the incidence of CIN was not high in Japanese patients with advanced renal dysfunction in routine clinical practice. Whereas, the long-term prognosis following PCI is observed to be poor in this studied population, and CIN did not show a significant prognostic influence.

Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury.

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

Omentin attenuates atherosclerotic lesion formation in apolipoprotein E-deficient mice.

AIMS: Obesity is associated with the development of atherosclerosis. We previously demonstrated that omentin is a circulating adipokine that is downregulated in association with atherosclerotic diseases. Here, we examined the impact of omentin on the development of atherosclerosis with gain-of-function genetic manipulations and dissected its potential mechanism. METHODS AND RESULTS: Apolipoprotein E-deficient (apoE-KO) mice were crossed with transgenic mice expressing the human omentin gene (OMT-Tg) mice in fat tissue to generate apoE-KO/OMT-Tg mice. ApoE-KO/OMT-Tg mice exhibited a significant reduction of the atherosclerotic areas in aortic sinus, compared with apoE-KO mice despite similar lipid levels. ApoE-KO/OMT-Tg mice also displayed significant decreases in macrophage accumulation and mRNA expression of proinflammatory mediators including tumour necrosis factor-α, interleukin-6, and monocyte chemotactic protein-1 in aorta when compared with apoE-KO mice. Treatment of human monocyte-derived macrophages with a physiological concentration of human omentin protein led to reduction of lipid droplets and cholesteryl ester content. Treatment with human omentin protein also reduced lipopolysaccharide-induced expression of proinflammatory genes in human macrophages. Treatment of human macrophages with omentin promoted the phosphorylation of Akt. Inhibition of Akt signalling abolished the anti-inflammatory actions of omentin in macrophages. CONCLUSION: 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.

Clinical benefit of tolvaptan in patients with acute decompensated heart failure and chronic kidney disease.

Tolvaptan, a vasopressin type 2 receptor antagonist, has an aquaretic effect without affecting renal function. The effects of long-term tolvaptan administration in heart failure patients with renal dysfunction have not been clarified. Here, we assessed the clinical benefit of tolvaptan during a 6-month follow-up in acute decompensated heart failure (ADHF) patients with severe chronic kidney disease (CKD; estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m(2)). We compared 33 patients with ADHF and severe CKD who were administered tolvaptan in addition to loop diuretics (TLV group), with 36 patients with ADHF and severe CKD who were administered high-dose loop diuretics (≥40 mg) alone (LD group). Alterations in serum creatinine and eGFR levels from the time of hospital discharge to 6-month follow-up were significantly different between the groups, with those in the TLV group being more favorable. Furthermore, Kaplan-Meier analysis revealed that rehospitalization for heart failure (HF) was significantly lower in the TLV group compared with the LD group. In ADHF patients with severe CKD, tolvaptan use for 6 months reduced worsening of renal function and rehospitalization rates for HF when compared with conventional diuretic therapy. In conclusion, tolvaptan could be a safe and effective agent for long-term management of HF and CKD.

C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart.

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.

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism.

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control ß-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

Neuron-derived neurotrophic factor ameliorates adverse cardiac remodeling after experimental myocardial infarction.

BACKGROUND: Myocardial infarction (MI) is one of the major causes of death worldwide. Chronic heart failure is a serious complication of MI that leads to poor prognosis. We recently found that neuron-derived neurotrophic factor (NDNF) is a proangiogenic secretory protein that is upregulated in ischemic skeletal muscle. Here, we examined whether NDNF modulates cardiac remodeling in response to chronic ischemia. METHODS AND RESULTS: C57BL/6J wild-type mice were subjected to the permanent ligation of the left anterior descending coronary artery to create MI. Adenoviral vectors expressing NDNF or ß-galactosidase (control) were intramuscularly injected into mice 3 days before permanent left anterior descending coronary artery ligation. Intramuscular administration of adenoviral vectors expressing NDNF to mice resulted in increased levels of circulating NDNF. Adenoviral vectors expressing NDNF administration improved left ventricular systolic dysfunction and dilatation after MI surgery. Moreover, adenoviral vectors expressing NDNF enhanced capillary formation and reduced cardiomyocyte apoptosis and hypertrophy in the post-MI hearts. Treatment of cultured cardiomyocytes with recombinant NDNF protein led to reduced apoptosis under conditions of hypoxia. NDNF also promoted the phosphorylation of Akt and focal adhesion kinase in cardiomyocytes. Blockade of focal adhesion kinase activation blocked the stimulatory effects of NDNF on cardiomyocyte survival and Akt phosphorylation. Similarly, treatment of cultured endothelial cells with NDNF protein led to enhancement of network formation and Akt phosphorylation, which was diminished by focal adhesion kinase inhibition. CONCLUSIONS: These data suggest that NDNF ameliorates adverse myocardial remodeling after MI by its abilities to enhance myocyte survival and angiogenesis in the heart through focal adhesion kinase/Akt-dependent mechanisms.

Cardiac myocyte-derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model.

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-α 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-α-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.

Omentin functions to attenuate cardiac hypertrophic response.

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy.

Adipose-derived protein omentin prevents neointimal formation after arterial injury.

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control ß-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.

Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury.

AIMS: It is well-established that exercise diminishes cardiovascular risk, but whether humoral factors secreted by muscle confer these benefits has not been conclusively shown. We have shown that the secreted protein follistatin-like 1 (Fstl1) has beneficial actions on cardiac and endothelial function. However, the role of muscle-derived Fstl1 in proliferative vascular disease remains largely unknown. Here, we investigated whether muscle-derived Fstl1 modulates vascular remodelling in response to injury. METHODS AND RESULTS: The targeted ablation of Fstl1 in muscle led to an increase in neointimal formation following wire-induced arterial injury compared with control mice. Conversely, muscle-specific Fstl1 transgenic (TG) mice displayed a decrease in the neointimal thickening following arterial injury. Muscle-specific Fstl1 ablation and overexpression increased and decreased, respectively, the frequency of BrdU-positive proliferating cells in injured vessels. In cultured human aortic smooth muscle cells (HASMCs), treatment with human FSTL1 protein decreased proliferation and migration induced by stimulation with PDGF-BB. Treatment with FSTL1 enhanced AMPK phosphorylation, and inhibition of AMPK abrogated the inhibitory actions of FSTL1 on HASMC responses to PDGF-BB. The injured arteries of Fstl1-TG mice exhibited an increase in AMPK phosphorylation, and administration of AMPK inhibitor reversed the anti-proliferative actions of Fstl1 on the vessel wall. CONCLUSION: 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.