SPRR1A is a key downstream effector of MiR-150 during both maladaptive cardiac remodeling in mice and human cardiac fibroblast activation.

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 ß-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.

Financial Impact of the Indiana University Student-Run Free Clinic.

Student-run free clinics (SRFCs) serve as an important public safety-net for un- and under-insured patients. Few studies have investigated their financial impact or return of investment to the community. The aim of this study was to estimate the financial impact of the Indiana University Student Outreach Clinic (IUSOC) using national market values of medical visits and lab services in 2021.From internal triage classification records maintained from March to December 2021, Current Procedural Terminology (CPT) codes were assigned corresponding to "New Patient," "Returning Quick or Long" and "Fast Track" visits. Total Work Relative Value Units (wRVUs) were calculated to then estimate the total monetary value for medical services. Similarly, the collection of laboratory services rendered from March to December 2021 were assigned costs using the 2021 Center for Medicare and Medicaid Services (CMS) fee schedule.There were a total of 1475 medical visits identified in this study under the triage categories of interest, with 440 New Patient visits, 1032 Returning Quick and Long visits, and 3 Fast Track visits. From the calculated total wRVUs, the estimated monetary value for medical services was $95,413.79. Additionally, there were 3633 eligible lab tests ordered; almost half of these (1523, 41.9%) were categorized as routine lab tests (CMP, BMP, CBC, lipid panel). The estimated value of lab services was $56,296.81.Our estimates reveal that the IUSOC provided nearly $150,000 worth of free healthcare to the community in 2021. Further, most patients were seen for return visits, revealing the opportunity to streamline logistics.

Noncoding RNAs as Key Regulators for Cardiac Development and Cardiovascular Diseases.

Noncoding RNAs (ncRNAs) play fundamental roles in cardiac development and cardiovascular diseases (CVDs), which are a major cause of morbidity and mortality. With advances in RNA sequencing technology, the focus of recent research has transitioned from studies of specific candidates to whole transcriptome analyses. Thanks to these types of studies, new ncRNAs have been identified for their implication in cardiac development and CVDs. In this review, we briefly describe the classification of ncRNAs into microRNAs, long ncRNAs, and circular RNAs. We then discuss their critical roles in cardiac development and CVDs by citing the most up-to-date research articles. More specifically, we summarize the roles of ncRNAs in the formation of the heart tube and cardiac morphogenesis, cardiac mesoderm specification, and embryonic cardiomyocytes and cardiac progenitor cells. We also highlight ncRNAs that have recently emerged as key regulators in CVDs by focusing on six of them. We believe that this review concisely addresses perhaps not all but certainly the major aspects of current progress in ncRNA research in cardiac development and CVDs. Thus, this review would be beneficial for readers to obtain a recent picture of key ncRNAs and their mechanisms of action in cardiac development and CVDs.

MiR-150 blunts cardiac dysfunction in mice with cardiomyocyte loss of ß1-adrenergic receptor/ß-arrestin signaling and controls a unique transcriptome.

The ß1-adrenergic receptor (ß1AR) is found primarily in hearts (mainly in cardiomyocytes [CMs]) and ß-arrestin-mediated ß1AR signaling elicits cardioprotection through CM survival. We showed that microRNA-150 (miR-150) is upregulated by ß-arrestin-mediated ß1AR signaling and that CM miR-150 inhibits maladaptive remodeling post-myocardial infarction. Here, we investigate whether miR-150 rescues cardiac dysfunction in mice bearing CM-specific abrogation of ß-arrestin-mediated ß1AR signaling. Using CM-specific transgenic (TG) mice expressing a mutant ß1AR (G protein-coupled receptor kinase [GRK]-ß1AR that exhibits impairment in ß-arrestin-mediated ß1AR signaling), we first generate a novel double TG mouse line overexpressing miR-150. We demonstrate that miR-150 is sufficient to improve cardiac dysfunction in CM-specific GRK-ß1AR TG mice following chronic catecholamine stimulation. Our genome-wide circular RNA, long noncoding RNA (lncRNA), and mRNA profiling analyses unveil a subset of cardiac ncRNAs and genes as heretofore unrecognized mechanisms for beneficial actions of ß1AR/ß-arrestin signaling or miR-150. We further show that lncRNA Gm41664 and GDAP1L1 are direct novel upstream and downstream regulators of miR-150. Lastly, CM protective actions of miR-150 are attributed to repressing pro-apoptotic GDAP1L1 and are mitigated by pro-apoptotic Gm41664. Our findings support the idea that miR-150 contributes significantly to ß1AR/ß-arrestin-mediated cardioprotection by regulating unique ncRNA and gene signatures in CMs.

MiR-150 Attenuates Maladaptive Cardiac Remodeling Mediated by Long Noncoding RNA MIAT and Directly Represses Profibrotic Hoxa4.

BACKGROUND: MicroRNA-150 (miR-150) plays a protective role in heart failure (HF). Long noncoding RNA, myocardial infarction-associated transcript (MIAT) regulates miR-150 function in vitro by direct interaction. Concurrent with miR-150 downregulation, MIAT is upregulated in failing hearts, and gain-of-function single-nucleotide polymorphisms in MIAT are associated with increased risk of myocardial infarction (MI) in humans. Despite the correlative relationship between MIAT and miR-150 in HF, their in vivo functional relationship has never been established, and molecular mechanisms by which these 2 noncoding RNAs regulate cardiac protection remain elusive. METHODS: We use MIAT KO (knockout), Hoxa4 (homeobox a4) KO, MIAT TG (transgenic), and miR-150 TG mice. We also develop DTG (double TG) mice overexpressing MIAT and miR-150. We then use a mouse model of MI followed by cardiac functional, structural, and mechanistic studies by echocardiography, immunohistochemistry, transcriptome profiling, Western blotting, and quantitative real-time reverse transcription-polymerase chain reaction. Moreover, we perform expression analyses in hearts from patients with HF. Lastly, we investigate cardiac fibroblast activation using primary adult human cardiac fibroblasts and in vitro assays to define the conserved MIAT/miR-150/HOXA4 axis. RESULTS: Using novel mouse models, we demonstrate that genetic overexpression of MIAT worsens cardiac remodeling, while genetic deletion of MIAT protects hearts against MI. Importantly, miR-150 overexpression attenuates the detrimental post-MI effects caused by MIAT. Genome-wide transcriptomic analysis of MIAT null mouse hearts identifies Hoxa4 as a novel downstream target of the MIAT/miR-150 axis. Hoxa4 is upregulated in cardiac fibroblasts isolated from ischemic myocardium and subjected to hypoxia/reoxygenation. HOXA4 is also upregulated in patients with HF. Moreover, Hoxa4 deficiency in mice protects the heart from MI. Lastly, protective actions of cardiac fibroblast miR-150 are partially attributed to the direct and functional repression of profibrotic Hoxa4. CONCLUSIONS: Our findings delineate a pivotal functional interaction among MIAT, miR-150, and Hoxa4 as a novel regulatory mechanism pertinent to ischemic HF.

Cardiomyocyte microRNA-150 confers cardiac protection and directly represses proapoptotic small proline-rich protein 1A.

MicroRNA-150 (miR-150) is downregulated in patients with multiple cardiovascular diseases and in diverse mouse models of heart failure (HF). miR-150 is significantly associated with HF severity and outcome in humans. We previously reported that miR-150 is activated by ß-blocker carvedilol (Carv) and plays a protective role in the heart using a systemic miR-150 KO mouse model. However, mechanisms that regulate cell-specific miR-150 expression and function in HF are unknown. Here, we demonstrate that potentially novel conditional cardiomyocyte-specific (CM-specific) miR-150 KO (miR-150 cKO) in mice worsens maladaptive cardiac remodeling after myocardial infarction (MI). Genome-wide transcriptomic analysis in miR-150 cKO mouse hearts identifies small proline-rich protein 1a (Sprr1a) as a potentially novel target of miR-150. Our studies further reveal that Sprr1a expression is upregulated in CMs isolated from ischemic myocardium and subjected to simulated ischemia/reperfusion, while its expression is downregulated in hearts and CMs by Carv. We also show that left ventricular SPRR1A is upregulated in patients with HF and that Sprr1a knockdown in mice prevents maladaptive post-MI remodeling. Lastly, protective roles of CM miR-150 are, in part, attributed to the direct and functional repression of proapoptotic Sprr1a. Our findings suggest a crucial role for the miR-150/SPRR1A axis in regulating CM function post-MI.