A role for T lymphocytes in mediating cardiac diastolic function

Abstract

The induction of T helper (TH) lymphocytes by distinct TH ligands results in a differentiation to TH1/TH2 subsets based on their unique pattern of cytokine secretion and effector functions. We hypothesized that the relative proportion of TH1/TH2 directly relates to cardiac fibroblast (CF) function and thereby cardiac extracellular matrix (ECM) composition and cardiac diastolic function in the absence of injury or altered wall stress. We compared the effect of selective TH1 with TH2 inducers on cardiac gene expression, ECM composition, and diastolic function in C57BL/J mice. Twelve weeks after immune modulation, the left ventricular stiffness (beta) was significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). The TH2 group also demonstrated significantly increased end-diastolic and end-systolic volumes (P < 0.01). Cardiac gene expression patterns for pro-matrix metalloproteinase (MMP)-9 and -13 were increased by greater than fivefold in the TH2 group and significantly decreased in the TH1 group (P < 0.05). The total cardiac collagen and cross-linked collagen were significantly increased in the TH1 group and decreased in the TH2 group (P < 0.01). Coculturing lymphocytes harvested from the treated mice with naive primary CF demonstrated a direct control of the lymphocytes on CF pro-collagen, pro-MMP gene expression, and MMP activity. These results suggest that the TH phenotype differentially affects diastolic function through modulating CF pro-collagen and pro-MMP gene expression, MMP activity, and cardiac collagen cross-linking, resulting in altered ECM composition. Thus modulation of TH lymphocyte function could promote adaptive remodeling in heart failure and postmyocardial infarction.

Age- and gender-dependent myocardial transcription patterns of cytokines and extracellular matrix remodelling enzymes in cats with non-cardiac diseases

“…Femalecats exhibited a reduction of IL-1, IL-2, IL-4, IL-6, IFN-γ, MMP-3 and TIMP-2 with age,in male cats this applied for IL-6, MMP-2 and TIMP-1.Conflicting results are reported for the role of immune modulatory cytokines in cardiac remodelling. In mouse models, Th2 induction resulted in reduced ventricular stiffness, and Th1 cells were involved in initiation of fibrosis and collagen crosslinking (Yu et al, 2005;, whereasanother 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 21 study did detecta shift from Th1 to Th2 response in old mice in association with interstitial myocardial fibrosis (Cieslik et al, 2011). We observed a reduction of all three immune modulatory markers (IL-2, IL-4,IFN-γ)with age in thefemale cats, which might be consistent with a generally reduced myocardial inflammatory response, as suggested by thereduced transcriptionof IL-1 and IL-6.Aupperle and co-authors (2011) observed reduced TIMP-2 expression in association with myocardial fibrosis in cats.In older sheep (> 8 years), rat and mouse models, higher myocardial MMP-2 and reduced TIMP-2 mRNA and protein expression, as well as cardiomyocyte hypertrophy and perivascular and interstitial fibrosis, imbalanced cardiac remodelling and impaired repair was observed (Kandalam et al, 2010;Wang et al, 2010;Horn et al, 2012;Givvimani et al, 2013).…”

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

“…7 Thus, we favor a third, and novel, explanation: that the absence of TIMP-1 may alter the anatomical distribution of activated immune cells, mitigating their immunopathological effects in the heart. A previous study has shown that activated immune cells produce and secrete MMPs to disrupt the extracellular matrix, thereby facilitating their entry into cardiac tissue 42 ; another report showed that the administration of recombinant TIMP-1 arrests the migration of immune cells in vitro. 43 Furthermore, an adenovirus-mediated increase in TIMP-1 expression also resulted in diminished CVB3-induced myocarditis.…”

IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice

“…Hydroxylproline and cross-linking assays have been described by Yu et al (45). Hydroxylproline levels were quantified by comparison to a standard colorimetric curve of trans-hydroxylproline (Sigma).…”

“…The isolation and culture of cardiac fibroblasts were performed as described by Yu et al (45). At 80 -90% confluence, cardiac fibroblasts were treated with 10 ng/ml rIL-18, 1:10 diluted supernatants from splenic T lymphocytes (described below), or 10 g/ml CpG 1668.…”

“…Splenic T lymphocytes were isolated and cultured according to the methods reported by Yu et al (45). After 48 h of treatment with 10 g/ml CpG 1668, supernatants were collected as conditioned medium.…”