Dataset Information

Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction.

ABSTRACT: Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II-induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4-deficient Balb/c mice (IL-4(-/-)) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/interstitial collagen fraction), enlarged left ventricle chamber, and declined cardiac function associated with a greater number of mast cells and macrophages in the heart compared with IL-4(-/-). In contrast, IL-4(-/-) mice had normal cardiac architecture/function while showing a 57.9% reduction in heart interstitial collagen compared with WT, despite elevated proinflammatory cytokines in heart tissue. In response to angiotensin II administration, IL-4(-/-) had reduced interstitial myocardial fibrosis and were protected from developing dilated cardiomyopathy, which was seen in WT mice. This was associated with increased macrophage infiltration into the hearts of WT mice, despite a similar degree of hypertension and increased cardiac transforming growth factor-?1 in both groups. In vitro data demonstrated that IL-4 upregulates procollagen genes and stimulates collagen production in mouse cardiac fibroblasts. This process is mediated by signal transducer and activator of transcription 6 signaling pathway via IL-4 receptor alpha. This study not only establishes a causal relationship between IL-4 and cardiac fibrosis/dysfunction, but also reveals a critical role for IL-4 in angiotensin II-induced cardiac damage. IL-4 could serve as an additional target for the treatment of cardiac fibrosis.

SUBMITTER: Peng H

PROVIDER: S-EPMC4685692 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction.

Peng Hongmei H Sarwar Zeyd Z Yang Xiao-Ping XP Peterson Edward L EL Xu Jiang J Janic Branislava B Rhaleb Nadia N Carretero Oscar A OA Rhaleb Nour-Eddine NE

Hypertension (Dallas, Tex. : 1979) 20150720 3

Elevated interleukin-4 (IL-4) levels are associated with cardiac fibrosis in hypertension and heart failure in both patients and experimental animals. We hypothesized that chronically elevated IL-4 induces cardiac fibrosis, resulting in a predisposition of the heart to angiotensin II-induced damage. Wild-type Balb/c (WT, high circulating IL-4) and IL-4-deficient Balb/c mice (IL-4(-/-)) were used. WT mice exhibited cardiac fibrosis (evidenced by an increase in expression of procollagen genes/inte ...[more]

PMID: 26195478

Similar Datasets

Project description:BackgroundHeart failure is a leading cause of death worldwide. Cyclic nucleotide phosphodiesterases (PDEs), through degradation of cyclic nucleotides, play critical roles in cardiovascular biology and disease. Our preliminary screening studies have revealed PDE10A upregulation in the diseased heart. However, the roles of PDE10A in cardiovascular biology and disease are largely uncharacterized. The current study is aimed to investigate the regulation and function of PDE10A in cardiac cells and in the progression of cardiac remodeling and dysfunction.MethodsWe used isolated adult mouse cardiac myocytes and fibroblasts, as well as preclinical mouse models of hypertrophy and heart failure. The PDE10A selective inhibitor TP-10, and global PDE10A knock out mice were used.ResultsWe found that PDE10A expression remains relatively low in normal and exercised heart tissues. However, PDE10A is significantly upregulated in mouse and human failing hearts. In vitro, PDE10A deficiency or inhibiting PDE10A with selective inhibitor TP-10, attenuated cardiac myocyte pathological hypertrophy induced by Angiotensin II, phenylephrine, and isoproterenol, but did not affect cardiac myocyte physiological hypertrophy induced by IGF-1 (insulin-like growth factor 1). TP-10 also reduced TGF-? (transforming growth factor-?)-stimulated cardiac fibroblast activation, proliferation, migration and extracellular matrix synthesis. TP-10 treatment elevated both cAMP and cGMP levels in cardiac myocytes and cardiac fibroblasts, consistent with PDE10A as a cAMP/cGMP dual-specific PDE. In vivo, global PDE10A deficiency significantly attenuated myocardial hypertrophy, cardiac fibrosis, and dysfunction induced by chronic pressure overload via transverse aorta constriction or chronic neurohormonal stimulation via Angiotensin II infusion. Importantly, we demonstrated that the pharmacological effect of TP-10 is specifically through PDE10A inhibition. In addition, TP-10 is able to reverse pre-established cardiac hypertrophy and dysfunction. RNA-Sequencing and bioinformatics analysis further identified a PDE10A-regualted transcriptome involved in cardiac hypertrophy, fibrosis, and cardiomyopathy.ConclusionsTaken together, our study elucidates a novel role for PDE10A in the regulation of pathological cardiac remodeling and development of heart failure. Given that PDE10A has been proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy for preventing and treating cardiac diseases associated with cardiac remodeling.

Project description:Heart Failure (HF) is the leading cause of death worldwide. Myocardial fibrosis, one of the clinical manifestations implicated in almost every form of heart disease, contributes significantly to HF development. However, there is no approved drug specifically designed to target cardiac fibrosis. Nintedanib (NTB) is an FDA approved tyrosine kinase inhibitor for idiopathic pulmonary fibrosis (IPF) and chronic fibrosing interstitial lung diseases (ILD). The favorable clinical outcome of NTB in IPF patients is well established. Furthermore, NTB is well tolerated in IPF patients irrespective of cardiovascular comorbidities. However, there is a lack of direct evidence to support the therapeutic efficacy and safety of NTB in cardiac diseases. In this study we examined the effects of NTB treatment on cardiac fibrosis and dysfunction using a murine model of HF. Specifically, 10 weeks old C57BL/6J male mice were subjected to Transverse Aortic Constriction (TAC) surgery. NTB was administered once daily by oral gavage (50 mg/kg) till 16 weeks post-TAC. Cardiac function was monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 16 weeks post-TAC. In the control group, systolic dysfunction started developing from 4 weeks post-surgery and progressed till 16 weeks. However, NTB treatment prevented TAC-induced cardiac functional decline. In another experiment, NTB treatment was stopped at 8 weeks, and animals were followed till 16 weeks post-TAC. Surprisingly, NTB's beneficial effect on cardiac function was maintained even after treatment interruption. NTB treatment remarkably reduced cardiac fibrosis as confirmed by Masson's trichrome staining and decreased expression of collagen genes (COL1A1, COL3A1). Compared to the TAC group, NTB treated mice showed a lower HW/TL ratio and cardiomyocyte cross-sectional area. NTB treatment reduced myocardial and systemic inflammation by inhibiting pro-inflammatory subsets and promoting regulatory T cells (Tregs). Our in vitro studies demonstrated that NTB prevents myofibroblast transformation, TGFβ1-induced SMAD3 phosphorylation, and the production of fibrogenic proteins (Fibronectin-1, α-SMA). However, NTB promoted immunosuppressive phenotype in Tregs, and altered vital signaling pathways in isolated cardiac fibroblast and cardiomyocytes, suggesting that its biological effect and underlying cardiac protection mechanisms are not limited to fibroblast and fibrosis alone. Our findings provide a proof of concept for repurposing NTB to combat adverse myocardial fibrosis and encourage the need for further validation in large animal models and subsequent clinical development for HF patients.

Dataset Information

Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction.

Publications

Profibrotic Role for Interleukin-4 in Cardiac Remodeling and Dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets