tranilast and Cardiomyopathies

Cardiomyopathy is the leading cause of death in patients with muscular dystrophy (MD). Tranilast, a widely used anti-allergic drug, has displayed inhibitory activity against the transient receptor potential cation channel subfamily V member 2 and improved cardiac function in MD patients. To identify urinary biomarkers that assess improved cardiac function after tranilast administration, we performed a urinary metabolomic study focused on oxidative fatty acids. Accompanying the clinical trial of tranilast, urine specimens were collected over 24 weeks from MD patients with advanced heart failure. Urinary levels of tetranor-PGDM (tetranor-prostaglandin D metabolite), a metabolite of prostaglandin D

Topics: Biomarkers; Cardiomyopathies; Heart Failure; Humans; Muscular Dystrophies; ortho-Aminobenzoates; TRPV Cation Channels

Tranilast has an ameliorative effect on myocardial fibrosis (MF), but the specific mechanism has not been studied. S100A11 is a key regulator of collagen expression in MF. In this paper, we will study the regulatory roles of Tranilast and S100A11 in MF. After the introduction of angiotensin II (AngII) to Human cardiac fibroblasts (HCF), Tranilast was administered. CCK-8 kit was used to detect cell viability. Wound Healing assay detected cell migration, and Western blot was used to detect the expression of migration-related proteins and proteins related to extracellular matrix synthesis. The expression of α-SMA was detected by immunofluorescence (IF). The expression of S100A11 was detected by qPCR and Western blot, and then S100A11 was overexpressed by cell transfection technology, so as to explore the mechanism by which Tranilast regulated MF. In addition, the expression of TGF-β1/Smad pathway related proteins was detected by Western blot. Tranilast inhibited Ang II-induced over-proliferation, migration and fibrosis of human cardiac fibroblasts (HCF), and simultaneously significantly decreased S100A11 expression was observed. Overexpression of S100A11 reversed the inhibition of Tranilast on AngII-induced over-proliferation, migration, and fibrosis in HCF, accompanied by activation of the TGF-β1/Smad pathway. Overall, Tranilast inhibits angiotensin II-induced myocardial fibrosis through S100A11/TGF-β1/Smad axis.

Topics: Angiotensin II; Cardiomyopathies; Cell Movement; Cell Survival; Cells, Cultured; Fibrosis; Humans; ortho-Aminobenzoates; S100 Proteins; Signal Transduction; Smad Proteins; Transforming Growth Factor beta1

Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.

Topics: Calcium Channel Blockers; Cardiomyopathies; Humans; Japan; Multicenter Studies as Topic; Muscular Dystrophies; ortho-Aminobenzoates

Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Heart; Humans; Muscular Dystrophy, Duchenne; ortho-Aminobenzoates

Topics: Cardiomyopathies; Cardiomyopathy, Dilated; Heart; Humans; Muscular Dystrophy, Duchenne; ortho-Aminobenzoates

Diastolic dysfunction is an increasingly recognized complication of diabetes that develops in relatively young patients as a result of diabetic cardiomyopathy (DCM). With recent advances in echocardiographic technology now permitting the reliable assessment of diastolic function in the rat, we examined cardiac function and structure in diabetic rodents and assessed the effects of intervening with tranilast, an antifibrotic compound that has been shown to attenuate the actions of transforming growth factor-beta (TGF-beta) in cardiac fibroblasts. We also sought to examine the mechanism whereby tranilast inhibits the actions of TGF-beta. Six-week-old heterozygous (mRen-2)27 rats were randomized to receive either streptozotocin or citrate buffer and then further randomized to receive either tranilast (400 mg x kg(-1) x day(-1) by twice daily gavage) or vehicle for another 8 wk. Cell signaling was examined in neonatal cardiac fibroblasts. After 8 wk, diabetic rats showed evidence of impaired diastolic function with reduced early-to-late atrial wave ratio and prolonged deceleration time in association with fibrosis, apoptosis, and hypertrophy (all P < 0.05). Treatment with tranilast prevented the development of diastolic dysfunction and the histopathological features of DCM. While tranilast did not affect Smad phosphorylation, it significantly attenuated TGF-beta-induced p44/42 mitogen-activated protein kinase phosphorylation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiomyopathies; Cytokines; Diabetes Complications; Diastole; Disease Models, Animal; Dose-Response Relationship, Drug; Female; ortho-Aminobenzoates; Rats; Streptozocin; Treatment Outcome; Ultrasonography; Ventricular Dysfunction, Left