Browsing by Subject "Ventricular remodeling"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Mapping cardiac remodeling in chronic kidney disease
    (American Association for the Advancement of Science, 2023) Kaesler, Nadine; Cheng, Mingbo; Nagai, James; O’Sullivan, James; Peisker, Fabian; Bindels, Eric M. J.; Babler, Anne; Moellmann, Julia; Droste, Patrick; Franciosa, Giulia; Dugourd, Aurelien; Saez-Rodriguez, Julio; Neuss, Sabine; Lehrke, Michael; Boor, Peter; Goettsch, Claudia; Olsen, Jesper V.; Speer, Thimoteus; Lu, Tzong-Shi; Lim, Kenneth; Floege, Jürgen; Denby, Laura; Costa, Ivan; Kramann, Rafael; Medicine, School of Medicine
    Patients with advanced chronic kidney disease (CKD) mostly die from sudden cardiac death and recurrent heart failure. The mechanisms of cardiac remodeling are largely unclear. To dissect molecular and cellular mechanisms of cardiac remodeling in CKD in an unbiased fashion, we performed left ventricular single-nuclear RNA sequencing in two mouse models of CKD. Our data showed a hypertrophic response trajectory of cardiomyocytes with stress signaling and metabolic changes driven by soluble uremia-related factors. We mapped fibroblast to myofibroblast differentiation in this process and identified notable changes in the cardiac vasculature, suggesting inflammation and dysfunction. An integrated analysis of cardiac cellular responses to uremic toxins pointed toward endothelin-1 and methylglyoxal being involved in capillary dysfunction and TNFα driving cardiomyocyte hypertrophy in CKD, which was validated in vitro and in vivo. TNFα inhibition in vivo ameliorated the cardiac phenotype in CKD. Thus, interventional approaches directed against uremic toxins, such as TNFα, hold promise to ameliorate cardiac remodeling in CKD.
  • Thumbnail Image
    Item
    SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation
    (Springer Nature, 2023-07-19) Kawaguchi, Satoshi; Moukette, Bruno; Sepúlveda, Marisa N.; Hayasaka, Taiki; Aonuma, Tatsuya; Haskell, Angela K.; Mah, Jessica; Liangpunsakul, Suthat; Tang, Yaoliang; Conway, Simon J.; Kim, Il-man; Anatomy, Cell Biology and Physiology, School of Medicine
    MicroRNA-150 (miR-150) is conserved between rodents and humans, is significantly downregulated during heart failure (HF), and correlates with patient outcomes. We previously reported that miR-150 is protective during myocardial infarction (MI) in part by decreasing cardiomyocyte (CM) apoptosis and that proapoptotic small proline-rich protein 1a (Sprr1a) is a direct CM target of miR-150. We also showed that Sprr1a knockdown in mice improves cardiac dysfunction and fibrosis post-MI and that Sprr1a is upregulated in pathological mouse cardiac fibroblasts (CFs) from ischemic myocardium. However, the direct functional relationship between miR-150 and SPRR1A during both post-MI remodeling in mice and human CF (HCF) activation was not established. Here, using a novel miR-150 knockout;Sprr1a-hypomorphic (Sprr1ahypo/hypo) mouse model, we demonstrate that Sprr1a knockdown blunts adverse post-MI effects caused by miR-150 loss. Moreover, HCF studies reveal that SPRR1A is upregulated in hypoxia/reoxygenation-treated HCFs and is downregulated in HCFs exposed to the cardioprotective β-blocker carvedilol, which is inversely associated with miR-150 expression. Significantly, we show that the protective roles of miR-150 in HCFs are directly mediated by functional repression of profibrotic SPRR1A. These findings delineate a pivotal functional interaction between miR-150 and SPRR1A as a novel regulatory mechanism pertinent to CF activation and ischemic HF.