The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential regulation of urokinase plasminogen activator

Davis, Darren R.; Wilson, Kate; Sam, Melissa; Kennedy, Seán; Mackman, Nigel; Charlesworth, J. A.; Erlich, Jonathan

doi:10.1016/j.yjmcc.2006.11.017

Cited by 18 publications

(17 citation statements)

References 38 publications

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“…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). The age-associated reduced TIMP-2 and MMP-2 transcription in female and male cats, respectively,suggests therefore a pro-fibrotic potential and impaired repair of the female myocardium, and further supports a reactive male myocardium facilitating appropriate repair (Davis et al, 2007;Chen and Frangogiannis, 2010).…”

Section: Discussionmentioning

confidence: 66%

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

Fonfara

Hetzel

Hahn

et al. 2015

Experimental Gerontology

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Background:Age, genderand systemic diseases all influence cardiac function and remodelling.In cats, age and genderassociated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whetherrelevant cytokines and extracellular matrix (ECM) remodellingenzymesare expressed in the myocardium of cats with non-cardiac diseasesand whether transcription levels are influenced by age and gender. Methods:The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire), nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects.All hearts were assessed for any pathological changes, and the myocardium was analysed for interleukin (IL)-1, -2, -4, -6, -18, tumour necrosis factor (TNF)-, interferon(IFN)-, transforming growth factor (TGF)-, matrix metalloproteinase (MMP)-2, -3, -13, tissue inhibitor of MMP (TIMP)-1, -2 and -3 transcription using quantitative RT-PCR assays. Results:Despite the absence of any histological evidence of myocardial damage,inflammation and fibrosis, the myocardium of all cats was found to constitutively transcribe cytokines and ECM remodelling enzymes, with generally higher mRNA concentrations in atria than in ventricles.Young and male cats exhibited higher transcription levels throughout the myocardium in comparison to older and female cats. Furthermore, age-associated transcription pattern differed between male and female cats. Conclusion:The constitutive transcription of ECM remodellingenzymes suggests continuous myocardial remodelling throughout the entire life of a cat. The myocardium of young and malecats appears to be in a pro-inflammatory state, whereas in older and female cats the myocardium exhibits a reduced inflammatory reaction to systemic disease.Age-associated cardiac remodelling seems to be influenced bynon-hormonal factors inmale and female cats. Abstract: Background: Age, gender and systemic diseases all influence cardiac function and remodelling. In cats, age and gender associated myocardial remodelling and the effect of systemic diseases on the myocardium have so far not been studied. The aim of the study was therefore to investigate whether relevant cytokines and extracellular matrix (ECM) remodelling enzymes are expressed in the myocardium of cats with non-cardiac diseases and whether transcription levels are influenced by age and gender. Methods: The study was performed on myocardial samples from 26 cats aged between 2 and 19 years that had died with non-cardiac diseases. Seventeen cats were female (2 entire), nine were male (1 entire). Of these, nine cats were diagnosed with diseases unlikely to affect the myocardium (control cats). The remaining 17 cats suffered from diseases with likely systemic effects. All hearts were assessed fo...

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Section: Discussionmentioning

confidence: 66%

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

Fonfara

Hetzel

Hahn

et al. 2015

Experimental Gerontology

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“…Consistent with prior findings in aged mice with life-long deficits in other key hemostatic factors (eg, TF, 43 fX, 44 fVII, 45 fXIII 46 ), the hearts of aged Mx Ϫ fII lox/Ϫ mice exhibited evidence of both hemosiderin deposition and cardiac fibrosis (modest and focal; Document S1, available on the Blood website; see the Supplemental Materials link at the top of the online article). Like low TF mice 47 and fXIII-deficient animals, 46 cardiac fibrotic changes were generally more appreciable in year-old Mx Ϫ fII lox/Ϫ males but also observed in older Mx Ϫ fII lox/Ϫ females. No overt clinical disorders or appreciable loss of fertility was noted in older Mx Ϫ fII lox/Ϫ mice of either gender relative to control mice.…”

Section: Loss Of Prothrombin In Adult Mice Results In Fatal Hemorrhagmentioning

confidence: 87%

Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain

Mullins¹,

Kombrinck

Talmage

et al. 2009

Blood

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Mice carrying a conditional prothrombin knockout allele (fII lox ) were established to develop an experimental setting for exploring the importance of thrombin in the maintenance of vascular integrity, the inflammatory response, and disease processes in adult animals. In the absence of Cre-mediated recombination, homozygous fII lox/lox mice or compound heterozygous mice carrying one fII lox allele and one constitutive-null allele were viable. Young adults exhibited neither spontaneous bleeding events nor diminished reproductive success. However, the induction of Cre recombinase in fII lox mice using the poly I:C-inducible Mx1-Cre system resulted in the rapid and near-complete recombination of the fII lox allele within the liver, the loss of circulating prothrombin, and profound derangements in coagulation function. Consistent with the notion that thrombin regulates coagulation and inflammatory pathways, an additional early consequence of reducing prothrombin was impaired antimicrobial function in mice challenged with Staphylococcus aureus peritonitis. However, life expectancy in unchallenged adults genetically depleted of prothrombin was very short (~5-7 days). The loss of viability was associated with the development of severe hemorrhagic events within multiple tissues, particularly in the heart and brain.

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“…Forward: 5Ј-GAGGAAAACATTAA-GAAGGGCAA-3Ј, reverse: 5Ј-CGGCACAGGTCTTGATGA-3Ј for CTGF; forward: 5Ј-GCCGGTAGAAGATGAGGTCA-3Ј, reverse: 5Ј-GGGCTCCAATCCTGTCAATC-3Ј for ANP; forward: 5Ј-ATCT-CACGTTCAGCTGTGGTCA-3Ј, reverse: 5Ј-ACCACCGGCATCGT-GTTGGAT-3Ј for ␣-SKA; forward: 5Ј-TCTGCTCCTGCTTTCCTTA-3Ј, reverse: 5Ј-GGACTATGTGCCATCTTGGA-3Ј for BNP; forward: 5Ј-GCCAACACCAACCTGTCCAAGTTA-3Ј, reverse: 5Ј-TTCAAAG-GCTCTCCAGGTCTCAGGGC-3Ј for ␤-MHC (56); and forward: 5Ј-CGGCTACCACATCCAAGGAA-3Ј, reverse: 5Ј-GCTGGAATTAC-CGCGGCT-3Ј for 18S. The mRNA levels of fibrosis markers, collagen-III, fibronectin (FN), and tissue inhibitor of metalloproteinase (TIMP-1) were also measured, using primers as follows: collagen-III, forward 5Ј-cagctggccttcctcagact-3Јt, and reverse 5Ј-gctgtttttgcagtggtatgtaatg-3Ј; FN forward 5Ј-gctgctgggacttccacgt-3Ј and reverse 5Ј-tctgttccgggaggtgca-3Ј; and TIMP-1, forward and reverse primers as previously described (13). Each RNA sample was analyzed in duplicate by real-time PCR.…”

Section: Methodsmentioning

confidence: 99%

Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor

Wang

McLennan

Allen

et al. 2009

American Journal of Physiology-Cell Physiology

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The development of cardiac fibrosis in low tissue factor mice is gender-dependent and is associated with differential regulation of urokinase plasminogen activator

Cited by 18 publications

References 38 publications

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

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

Genetic elimination of prothrombin in adult mice is not compatible with survival and results in spontaneous hemorrhagic events in both heart and brain

Adverse effects of high glucose and free fatty acid on cardiomyocytes are mediated by connective tissue growth factor

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