Cardiotrophin 1 Is Involved in Cardiac, Vascular, and Renal Fibrosis and Dysfunction

Abstract

Abstract-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. 1-3 Cardiac hypertrophy is attributable to cardiomyocyte hypertrophy, the proliferation of interstitial fibroblasts, and increased depositions of extracellular matrix (ECM) components.4 Arterial stiffening is associated with decreased distensibility and modified wall structure mainly characterized by increased ECM. 5,6 Chronic kidney disease progression is generally associated with tubulointerstitial fibrosis. 7,8 Therefore, it is of paramount importance to identify common pathways able to trigger cardiovascular and renal fibrosis.Cardiotrophin 1 (CT-1) is an interleukin 6 superfamily member.9 Elevated CT-1 levels have been reported in HF and in hypertensive patients.10-12 Moreover, CT-1 positively correlates with left ventricular (LV) mass index and the serum concentration of carboxy-terminal propeptide of procollagen type I, a biomarker of collagen synthesis, 10 suggesting that CT-1 may contribute to the development of cardiomyocyte hypertrophy and fibrosis. Accordingly, CT-1 administration increases heart weight in mice. 13 Our group has characterized CT-1-induced cardiomyocyte survival and hypertrophy, 10,14 as well as CT-1...

Association of Cardiotrophin-1 With Myocardial Fibrosis in Hypertensive Patients With Heart Failure

“…More recently, it has been reported that chronic administration of CT-1 to normotensive rats is associated with enhanced myocardial deposition of collagen type I and III fibers, increased LV volume, and reduced LV ejection fraction. 9 In addition, CT-1 knockout mice display lower arterial fibrosis than age-matched control animals. 27 Collectively, these experimental data support a cardiovascular profibrotic role for CT-1.…”

“…In fact, in vivo studies performed in rats have shown that CT-1 induces fibrosis in different organs, including the heart. 9,10 Although CT-1 has been shown to be increased in the myocardium of patients with HF, 11,12 there are no available data on the mechanisms involved in its overproduction and its association with myocardial fibrosis in HF.…”

Absence of Cardiotrophin 1 Is Associated With Decreased Age-Dependent Arterial Stiffness and Increased Longevity in Mice

“…1 Our group has described that CT-1 induces cell proliferation, hypertrophy, and secretion of extracellular matrix proteins in aortic vascular smooth muscle cells (VSMCs) in vitro 2 and in vivo, 3 suggesting a role for CT-1 in arterial fibrosis and stiffness, which both are features of aging. Furthermore, elevated plasma concentrations of CT-1 have been reported in patients with a variety of diseases, including hypertension, 4 heart failure, 5 uns table angina, 6 myocardial infarction, 7 and aortic stenosis, 8 indicating that this cytokine may contribute to the development of cardiovascular pathologies associated with aging.…”

Stimulatory Effects of Cardiotrophin 1 on Atherosclerosis

“…7,33,34 Vascular media thickness and ECM contents, such as collagen, fibronectin, elastin, and matrix metalloproteinase, in VSMCs were increased by CT-1 treatment in rats. 11,12 Media thickness, wall fibrosis, and inflammation were lower in CT-1-deficient mice than in wild-type controls under a normal diet. 35 These findings indicated that CT-1 plays an important role in arteriosclerosis that consists of vascular remodeling, inflammation, and calcification with aging.…”

“…[7][8][9][10] CT-1 exerts cardiovascular remodeling induced by hypertensive and ischemic heart diseases and congestive heart failure, through its receptor complex glycoprotein 130 (gp130) and leukemia inhibitory factor receptor (LIFR). [11][12][13][14] Recently, CT-1 has been shown to be expressed in the intima in the early stages of atherosclerotic lesions in human carotid artery. 15 CT-1 stimulates the synthesis of inflammatory cytokines and proatherogenic molecules, such as interleukin-6, monocyte chemoattractant protein-1, and intercellular adhesion molecule-1, in human ECs.…”