Browsing by Author "Madhur, Meena S."
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Item Cardiomyocyte-restricted MIAT deletion is sufficient to protect against murine myocardial infarction(Springer Nature, 2025-02-20) Hayasaka, Taiki; Kawaguchi, Satoshi; Sepúlveda, Marisa N.; Teoh, Jian-Peng; Moukette, Bruno; Aonuma, Tatsuya; Madhur, Meena S.; Desai, Ankit A.; Liangpunsakul, Suthat; Conway, Simon J.; Kim, Il-Man; Anatomy, Cell Biology and Physiology, School of MedicineMyocardial infarction-associated transcript (MIAT), an intergenic long noncoding RNA (lncRNA), is conserved between rodents and humans and is directly linked to maladaptive cardiac remodeling in both patients and mouse models with various forms of heart failure (HF). We previously reported attenuation of cardiac stress, apoptosis, and fibrosis in a murine model of myocardial infarction (MI) with global MIAT ablation. Our transcriptomic profiling and mechanistic studies further revealed MIAT-induced activation of maladaptive genes, such as Hoxa4, Fmo2, Lrrn4, Marveld3, and Fat4. However, the source of MIAT and its contribution to MI and HF remain unknown. In this study, we generate a novel cardiomyocyte (CM)-specific MIAT conditional knockout mouse model, which exhibits improved cardiac function after MI. We further report that CM-specific MIAT ablation is sufficient to reduce cardiac damage, apoptosis, and fibrosis following chronic MI. Mechanistically, CM-specific MIAT deletion in mice leads to decreased expression of proapoptotic and pathological profibrotic genes, such as p53, Bak1, Col3a1, Col6a1, Postn, and Snail1 after chronic MI. These results enable us to begin to dissect cell-specific contributions to MIAT signaling and bolster the idea that MIAT plays a direct pathological role in CMs after MI.Item MicroRNA-150 Deletion from Adult Myofibroblasts Augments Maladaptive Cardiac Remodeling Following Chronic Myocardial Infarction(MDPI, 2024-12-22) Kawaguchi, Satoshi; Sepúlveda, Marisa N.; Teoh, Jian-peng; Hayasaka, Taiki; Moukette, Bruno; Aonuma, Tatsuya; Roh, Hyun Cheol; Madhur, Meena S.; Kim, Il-man; Anatomy, Cell Biology and Physiology, School of MedicineMicroRNA (miR: small noncoding RNA)-150 is evolutionarily conserved and is downregulated in patients with diverse forms of heart failure (HF) and in multiple mouse models of HF. Moreover, miR-150 is markedly correlated with the outcome of patients with HF. We previously reported that systemic or cardiomyocyte-derived miR-150 in mice elicited myocardial protection through the inhibition of cardiomyocyte death, without affecting neovascularization and T cell infiltration. Our mechanistic studies also showed that the protective roles of miR-150 in ischemic mouse hearts and human cardiac fibroblasts were, in part, attributed to the inhibition of fibroblast activation via the repression of multiple profibrotic genes. However, the extent to which miR-150 expression in adult myofibroblasts (MFs) modulates the response to myocardial infarction (MI) remains unknown. Here, we develop a novel 4-hydroxytamoxifen-inducible MF-specific miR-150 conditional knockout mouse model and demonstrate that the mouse line exhibits worse cardiac dysfunction after MI. Our studies further reveal that miR-150 ablation selectively in adult MFs exacerbates cardiac damage and apoptosis after chronic MI. Lastly, MF-specific miR-150 deletion in adult mice promotes the expression of proinflammatory and profibrotic genes as well as cardiac fibrosis following chronic MI. Our findings indicate a key protective role for MF-derived miR-150 in modulating post-MI responses.Item Targeting IL-33/ST2 Signaling Alters Cardiac Structure and Function in Hypertensive Heart Disease(Elsevier, 2024-12-18) Wassenaar, Jean W.; Smart, C. Duncan; Fehrenbach, Daniel J.; Agrawal, Vineet; Dungan, Matthew M.; Fortune, Niki L.; Zhong, Lin; Hemnes, Anna R.; Peebles, R. Stokes, Jr.; Miller, Francis J., Jr.; Doran, Amanda C.; Madhur, Meena S.; Medicine, School of Medicine