56 research outputs found
Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice
Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized
that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-
old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic,
inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase
chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth
muscle cells were treated with CT-1 (10
−9
mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic
modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased
arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased
levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins,
and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity
compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and
senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased
arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic,
senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the
aging proces
Cardiotrophin 1 is involved in cardiac, vascular, and renal fibrosis and dysfunction
Cardiotrophin 1 (CT-1), a cytokine belonging to the interleukin 6 family, is increased in hypertension and in
heart failure. We aimed to study the precise role of CT-1 on cardiac, vascular, and renal function; morphology; and
remodeling in early stages without hypertension. CT-1 (20 g/kg per day) or vehicle was administrated to Wistar rats
for 6 weeks. Cardiac and vascular functions were analyzed in vivo using M-mode echocardiography, Doppler, and echo
tracking device and ex vivo using a scanning acoustic microscopy method. Cardiovascular and renal histomorphology
were measured by immunohistochemistry, RT-PCR, and Western blot. Kidney functional properties were assessed by
serum creatinine and neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. Without
alterations in blood pressure levels, CT-1 treatment increased left ventricular volumes, reduced fractional shortening and
ejection fraction, and induced myocardial dilatation and myocardial fibrosis. In the carotid artery of CT-1–treated rats,
the circumferential wall stress-incremental elastic modulus curve was shifted leftward, and the acoustic speed of sound
in the aorta was augmented, indicating increased arterial stiffness. Vascular media thickness, collagen, and fibronectin
content were increased by CT-1 treatment. CT-1–treated rats presented unaltered serum creatinine concentrations but
increased urinary and serum neutrophile gelatinase-associated lipocalin and microalbuminuria/creatininuria ratio. This
paralleled a glomerular and tubulointerstitial fibrosis accompanied by renal epithelial-mesenchymal transition. CT-1 is
a new potent fibrotic agent in heart, vessels, and kidney able to induce cardiovascular-renal dysfunction independent
from blood pressure. Thus, CT-1 could be a new target simultaneously integrating alterations of heart, vessels, and
kidney in early stages of heart failure
Galectin-3 inhibition prevents adipose tissue remodelling in obesity
International audienceExtracellular matrix remodelling of the adipose tissue has a pivotal role in the pathophysiology of obesity. Galectin-3 (Gal-3) is increased in obesity and mediates inflammation and fibrosis in the cardiovascular system. However, the effects of Gal-3 on adipose tissue remodelling associated with obesity remain unclear. Male Wistar rats were fed either a high-fat diet (33.5% fat) or a standard diet (3.5% fat) for 6 weeks. Half of the animals of each group were treated with the pharmacological inhibitor of Gal-3, modified citrus pectin (MCP; 100 mg kg(-1) per day) in the drinking water. In adipose tissue, obese animals presented an increase in Gal-3 levels that were accompanied by an increase in pericellular collagen. Obese rats exhibited higher adipose tissue inflammation, as well as enhanced differentiation degree of the adipocytes. Treatment with MCP prevented all the above effects. In mature 3T3-L1 adipocytes, Gal-3 (10(-8 )m) treatment increased fibrosis, inflammatory and differentiation markers. In conclusion, Gal-3 emerges as a potential therapeutic target in adipose tissue remodelling associated with obesity and could have an important role in the development of metabolic alterations associated with obesity
Absence of cardiotrophin 1 is associated with decreased age-dependent arterial stiffness and increased longevity in mice
Cardiotrophin 1 (CT-1), an interleukin 6 family member, promotes fibrosis and arterial stiffness. We hypothesized
that the absence of CT-1 influences arterial fibrosis and stiffness, senescence, and life span. In senescent 29-month-
old mice, vascular function was analyzed by echotracking device. Arterial histomorphology, senescence, metabolic,
inflammatory, and oxidative stress parameters were measured by immunohistochemistry, reverse transcription polymerase
chain reaction, Western blot, and ELISA. Survival rate of wild-type and CT-1–null mice was studied. Vascular smooth
muscle cells were treated with CT-1 (10
−9
mol/L) for 15 days to analyze senescence. The wall stress-incremental elastic
modulus curve of old CT-1–null mice was shifted rightward as compared with wild-type mice, indicating decreased
arterial stiffness. Media thickness and wall fibrosis were lower in CT-1–null mice. CT-1–null mice showed decreased
levels of inflammatory, apoptotic, and senescence pathways, whereas telomere-linked proteins, DNA repair proteins,
and antioxidant enzyme activities were increased. CT-1–null mice displayed a 5-month increased median longevity
compared with wild-type mice. In vascular smooth muscle cells, chronic CT-1 stimulation upregulated apoptotic and
senescence markers and downregulated telomere-linked proteins. The absence of CT-1 is associated with decreased
arterial fibrosis, stiffness, and senescence and increased longevity in mice likely through downregulating apoptotic,
senescence, and inflammatory pathways. CT-1 may be a major regulator of arterial stiffness with a major impact on the
aging proces
Mechanisms responsible for increased circulating levels of galectin-3 in cardiomyopathy and heart failure
Galectin-3 is a biomarker of heart disease. However, it remains unknown whether increase in galectin-3 levels is dependent on aetiology or disease-associated conditions and whether diseased heart releases galectin-3 into the circulation. We explored these questions in mouse models of heart disease and in patients with cardiomyopathy. All mouse models (dilated cardiomyopathy, DCM; fibrotic cardiomyopathy, ischemia-reperfusion, I/R; treatment with β-adrenergic agonist isoproterenol) showed multi-fold increases in cardiac galectin-3 expression and preserved renal function. In mice with fibrotic cardiomyopathy, I/R or isoproterenol treatment, plasma galectin-3 levels and density of cardiac inflammatory cells were elevated. These models also exhibited parallel changes in cardiac and plasma galectin-3 levels and presence of trans-cardiac galectin-3 gradient, indicating cardiac release of galectin-3. DCM mice showed no change in circulating galectin-3 levels nor trans-cardiac galectin-3 gradient or myocardial inflammatory infiltration despite a 50-fold increase in cardiac galectin-3 content. In patients with hypertrophic cardiomyopathy or DCM, plasma galectin-3 increased only in those with renal dysfunction and a trans-cardiac galectin-3 gradient was not present. Collectively, this study documents the aetiology-dependency and diverse mechanisms of increment in circulating galectin-3 levels. Our findings highlight cardiac inflammation and enhanced β-adrenoceptor activation in mediating elevated galectin-3 levels via cardiac release in the mechanism
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