Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice

Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-month-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-month-old TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Mechanistically, TLR2 deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor Forkhead box protein O1 (FoxO1) and, in turn, to elevated expression of FoxO1 target genes involved in the regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contrastile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and the activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice

Association of the MMP1–1607 1G>2G, MMP3-1171 5A>6A and MMP9-1562 C>T genotypes with breast cancer susceptibility and clinicopathological characteristics.

<p>Association of the MMP1–1607 1G>2G, MMP3-1171 5A>6A and MMP9-1562 C>T genotypes with breast cancer susceptibility and clinicopathological characteristics.</p

Synergistic effect of collagenase-1 (MMP1), stromelysin-1 (MMP3) and gelatinase-B (MMP9) gene polymorphisms in breast cancer

<div><p>Background</p><p>Extracellular matrix degradation by matrix metalloproteinases (MMPs) is an important mechanism involved in tumor invasion and metastasis. Genetic variations of MMPs have shown association with multiple cancers. The present study is focused to elucidate the association of MMP-1, 3 and 9 genetic variants with respect to epidemiological and clinicopathological variables by haplotype, LD, MDR, survival in silico analyses among South Indian women.</p><p>Material and methods</p><p>MMP3–1171 5A/6A and MMP9–1562 C/T SNPs were genotyped by Allele specific polymerase chain reaction and MMP1-1607 1G/2G polymorphism by restriction fragment length polymorphism assays respectively, in 300 BC patients and age-matched 300 healthy controls. Statistical analysis was performed using the SNPStats and SPSS software. Linkage disequilibrium and gene-gene interactions were performed using Haploview and MDR software respectively. Further, transcription factor binding sites in the promoter regions of SNPs under study were carried out using AliBaba2.1 software.</p><p>Results</p><p>We have observed an increased frequency of 2G-allele of MMP1, 6A-allele of MMP3 and T-allele of MMP9 (p<0.05) respectively in BC subjects. The 2G-6A haplotype (minor alleles of MMP-1 and MMP-3 respectively) has shown an increased susceptibility to BC. Further, MMP polymorphisms were associated with the clinical characteristics of BC patients such as steroid hormone receptor status, lymph node involvement and metastasis. SNP combinations were in perfect LD in controls. MDR analysis revealed a positive interaction between the SNPs. 5-years survival rate and cox-regression analysis showed a significant association with clinicopathological variables.</p><p>Conclusion</p><p>Our results suggest that MMP1–1607 1G/2G, MMP3–1171 5A/6A and MMP9–1562 C/T gene polymorphisms have synergistic effect on breast cancer. The interactions of MMPs clinical risk factors such as lymph node involvement has shown a strong correlation and might influence the 5-years survival rate, suggesting their potential role in the breast carcinogenesis.</p></div

Genotype and allele frequencies distribution for MMP-1, MMP-3 and MMP-9 gene polymorphisms in controls and breast cancer subjects.

<p>Genotype and allele frequencies distribution for MMP-1, MMP-3 and MMP-9 gene polymorphisms in controls and breast cancer subjects.</p

Effect of the MMP-1, -3 & -9 polymorphisms on transcription factor binding sites.

<p>Effect of the MMP-1, -3 & -9 polymorphisms on transcription factor binding sites.</p

Pairwise linkage disequilibrium estimates in controls and cases group.

<p>Pairwise linkage disequilibrium estimates in controls and cases group.</p

Forward and reverse primers and PCR conditions for genotyping of selected polymorphic variants of MMP-1,-3 & -9 genes.

<p>Forward and reverse primers and PCR conditions for genotyping of selected polymorphic variants of MMP-1,-3 & -9 genes.</p

Clinicopathological parameters among the breast cancer patients.

<p>Clinicopathological parameters among the breast cancer patients.</p

Summary of gene-gene interaction by MDR analysis.

<p>Summary of gene-gene interaction by MDR analysis.</p