Browsing by Subject "Cardiac remodeling"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Computational pathology assessments of cardiac stromal remodeling: Clinical correlates and prognostic implications in heart transplantation
    (Elsevier, 2024-12-28) Peyster, Eliot G.; Yuan, Cai; Arabyarmohammadi, Sara; Lal, Priti; Feldman, Michael D.; Fu, Pingfu; Margulies, Kenneth B.; Madabhushi, Anant; Pathology and Laboratory Medicine, School of Medicine
    Background: The hostile immune environment created by allotransplantation can accelerate pathologic tissue remodeling. Both overt and indolent inflammatory insults propel this remodeling, but there is a paucity of tools for monitoring the speed and severity of remodeling over time. Methods: This retrospective cohort consisted of n = 2,167 digitized heart transplant biopsy slides along with records of prior inflammatory events and future allograft outcomes (cardiac death or allograft vasculopathy). Utilizing computational pathology analysis, biopsy images were analyzed to identify the pathologic stromal changes associated with future allograft loss or vasculopathy. Biopsy images were then analyzed to assess which historical inflammatory events drive progression of these pathologic stromal changes. Results: The top 5 features of pathologic stromal remodeling most associated with adverse allograft outcomes were also strongly associated with histories of both overt and indolent inflammatory events. Compared to controls, a history of high-grade or treated rejection was significantly associated with progressive pathologic remodeling and future adverse outcomes (32.9% vs 5.1%, p < 0.001). A history of recurrent low-grade rejection and Quilty lesions was also significantly associated with pathologic remodeling and adverse outcomes vs controls (12.7% vs 5.1%, p = 0.047). A history of high-grade or treated rejection in the absence of recurrent low-grade rejection history was not associated with pathologic remodeling or adverse outcomes (7.1% vs 5.1%, p = 0.67). Conclusions: A history of both traditionally treated and traditionally ignored alloimmune responses can predispose patients to pathologic allograft remodeling and adverse outcomes. Computational pathology analysis of allograft stroma yields translationally relevant biomarkers, identifying accelerated remodeling before adverse outcomes occur. Data availability: The data that support the findings of this study are presented in the manuscript and extended data sections. Unprocessed raw data are available from the corresponding author upon reasonable request. Source code for the stromal feature analysis pipeline is hosted on GitHub and freely available: https://github.service.emory.edu/CYUAN31/Pathomics_StromalBioMarker_in_Myocardium.git.
  • Thumbnail Image
    Item
    Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis
    (Springer, 2021-04-19) Dittrich, Gesine M.; Froese, Natali; Wang, Xue; Kroeger, Hannah; Wang, Honghui; Szaroszyk, Malgorzata; Malek‑Mohammadi, Mona; Cordero, Julio; Keles, Merve; Korf‑Klingebiel, Mortimer; Wollert, Kai C.; Geffers, Robert; Mayr, Manuel; Conway, Simon J.; Dobreva, Gergana; Bauersachs, Johann; Heineke, Joerg; Pediatrics, School of Medicine
    Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.
  • Thumbnail Image
    Item
    Interleukin-1α dependent survival of cardiac fibroblasts is associated with StAR/STARD1 expression and improved cardiac remodeling and function after myocardial infarction
    (Elsevier, 2021) Razin, Talya; Melamed-Book, Naomi; Argaman, Jasmin; Galin, Iris; Lowy, Yosef; Anuka, Eli; Naftali-Shani, Nili; Kandel-Kfir, Michal; Garfinkel, Benjamin P.; Brielle, Shlomi; Granot, Zvi; Apte, Ron N.; Conway, Simon J.; Molkentin, Jeffery D.; Kamari, Yehuda; Leor, Jonathan; Orly, Joseph; Pediatrics, School of Medicine
    Aims: One unaddressed aspect of healing after myocardial infarction (MI) is how non-myocyte cells that survived the ischemic injury, keep withstanding additional cellular damage by stress forms typically arising during the post-infarction inflammation. Here we aimed to determine if cell survival is conferred by expression of a mitochondrial protein novel to the cardiac proteome, known as steroidogenic acute regulatory protein, (StAR/STARD1). Further studies aimed to unravel the regulation and role of the non-steroidogenic cardiac StAR after MI. Methods and results: Following permanent ligation of the left anterior descending coronary artery in mouse heart, timeline western blot analyses showed that StAR expression corresponds to the inflammatory response to MI. Following the identification of StAR in mitochondria of cardiac fibroblasts in culture, confocal microscopy immunohistochemistry (IHC) identified StAR expression in left ventricular (LV) activated interstitial fibroblasts, adventitial fibroblasts and endothelial cells. Further work with the primary fibroblasts model revealed that interleukin-1α (IL-1α) signaling via NF-κB and p38 MAPK pathways efficiently upregulates the expression of the Star gene products. At the functional level, IL-1α primed fibroblasts were protected against apoptosis when exposed to cisplatin mimicry of in vivo apoptotic stress; yet, the protective impact of IL-1α was lost upon siRNA mediated StAR downregulation. At the physiological level, StAR expression was nullified during post-MI inflammation in a mouse model with global IL-1α deficiency, concomitantly resulting in a 4-fold elevation of apoptotic fibroblasts. Serial echocardiography and IHC studies of mice examined 24 days after MI revealed aggravation of LV dysfunction, LV dilatation, anterior wall thinning and adverse tissue remodeling when compared with loxP control hearts. Conclusions: This study calls attention to overlooked aspects of cellular responses evolved under the stress conditions associated with the default inflammatory response to MI. Our observations suggest that LV IL-1α is cardioprotective, and at least one mechanism of this action is mediated by induction of StAR expression in border zone fibroblasts, which renders them apoptosis resistant. This acquired survival feature also has long-term ramifications on the heart recovery by diminishing adverse remodeling and improving the heart function after MI.
  • Thumbnail Image
    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 Medicine
    MicroRNA (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.