AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1-mediated therapeutic ...angiogenesis is unknown. Here, we show for the first time that AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demonstrate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust recovery of myocardial function and contraction with increased survival, increased ejection fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by promoting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilomycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and therapeutic actions, indicating that autophagy acts upstream of and is essential for angiogenesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to activation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autophagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that maintaining or increasing autophagy is a highly innovative strategy to robustly boost the efficacy of therapeutic angiogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Certain nonmammalian species such as zebrafish have an elevated capacity for innate heart regeneration. Understanding how heart regeneration occurs in these contexts can help illuminate cellular and ...molecular events that can be targets for heart failure prevention or treatment. The epicardium, a mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebrafish. The extent to which different cell subpopulations or states facilitate heart regeneration requires research attention.
To dissect epicardial cell states and associated proregenerative functions, we performed single-cell RNA sequencing and identified 7 epicardial cell clusters in adult zebrafish, 3 of which displayed enhanced cell numbers during regeneration. We identified paralogs of
as factors associated with the extracellular matrix and largely expressed in cluster 1. We assessed
expression in published single-cell RNA sequencing data sets from different stages and injury states of murine and human hearts, and we performed molecular genetics to determine the requirements for
-expressing cells and functions of each
paralog.
A particular cluster of epicardial cells had the strongest association with regeneration and was marked by expression of
and
. The
paralogs are expressed in epicardial cells that enclose dedifferentiated and proliferating cardiomyocytes during regeneration. Induced genetic depletion of
-expressing cells or genetic inactivation of
altered deposition of the key extracellular matrix component hyaluronic acid, disrupted cardiomyocyte proliferation, and inhibited heart regeneration. We also found that
-expressing epicardial cells first emerge at the juvenile stage, when they associate with and are required for focused cardiomyocyte expansion events that direct maturation of the ventricular wall.
Our findings identify a subset of epicardial cells that emerge in postembryonic zebrafish and sponsor regions of active cardiomyogenesis during cardiac growth and regeneration. We provide evidence that, as the heart achieves its mature structure, these cells facilitate hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. They are also required, along with the function of
paralog, in the production and organization of hyaluronic acid-containing matrix in cardiac injury sites, enabling normal cardiomyocyte proliferation and muscle regeneration.
Although screenings for breast and colorectal cancer are widely recommended, patient screening rates vary greatly and remain below public health targets, and primary care physicians' (PCPs') ...counseling and referrals play critical roles in patients' use of cancer screenings. Recent adverse events may influence PCPs' decision-making, but it remains unknown whether cancer screening rates of PCPs' patients change after PCPs are exposed to new cancer diagnoses.
To investigate whether PCPs' exposures to patients with new diagnoses of breast or colorectal cancer were associated with changes in screening rates for other patients subsequently visiting the affected PCPs.
This cohort study used stacked difference-in-differences analyses of all-payer claims data for New Hampshire and Maine in 2009 to 2015. Participants were PCPs caring for patients. Data analysis was performed from June 2020 to May 2022.
New diagnosis of a PCP's patient with breast cancer or colorectal cancer.
Patients' breast and colorectal cancer screening rates within 1 year of a PCP visit.
The sample included 3158 PCPs (1819 male PCPs 57.6%) caring for 1 920 189 patients (1 073 408 female patients 55.9%; mean SD age, 41.0 21.9 years) aged 18 to 64 years. During the study period, 898 PCPs had a patient with a new diagnosis of breast cancer and 370 PCPs had a patient with a new diagnosis of colorectal cancer. In the preexposure period, 68 837 female patients (37.3% of those visiting a PCP) underwent breast cancer screening within 1 year of the visit, and 13 137 patients (10.1% of those visiting a PCP) underwent colorectal cancer screening within 1 year of the visit. For both cancer types, after exposure to a new cancer diagnosis, PCPs' cancer screening rates displayed a rapid, sustained increase. Breast cancer screening rates increased by 4.5 percentage points (95% CI, 3.0-6.1 percentage points; P < .001). Colorectal cancer screening rates increased by 1.3 percentage points (95% CI, 0.3-2.2 percentage points; P = .01). Observed breast cancer screening increases were higher for male PCPs than for female PCPs (3.1 percentage points; 95% CI, 0.4-5.8 percentage points; P = .03).
This study found significant, sustained increases in cancer screening rates for patients visiting PCPs recently exposed to new breast and colorectal cancer diagnoses. These findings suggest that PCPs may update practice patterns on the basis of recent patient diagnoses. Future work should assess whether salient cues to PCPs about patient diagnoses when clinically appropriate can improve screening practices.
Summary
Recent genome‐wide single nucleotide polymorphism (SNP) association studies (GWAS) have identified a number of SNPs that were significantly associated with coronary artery disease and ...myocardial infarction (MI). However, many independent replication studies in other populations are needed to unequivocally confirm the GWAS association. To assess GWAS association, we have established a case‐control cohort consisting of 1231 well‐characterised MI patients and 560 controls without detectable coronary stenosis, all selected from the Cleveland Genebank population. The Genebank cohort has sufficient power to detect the association between MI and four GWAS SNPs, including rs17465637 within the MIA3 gene, rs2943634 (intergenic), rs6922269 in MTHFD1L, and rs599839 near SORT1. SNPs were genotyped by TaqMan assays and follow‐up multivariate logistic regression analysis with incorporation of significant covariates showed significant association with MI for MIA3 SNP rs17465637 (P‐adj= 0.0034) and SORT1 SNP rs599839 (P‐adj= 0.009). The minor allele G of rs599839 was also associated with a decreased LDL‐C level of 5–9 mg/dL per allele, but not with HDL‐C or triglyceride levels. No association for MI or lipid levels was found for SNPs rs2943634 and rs6922269 (P‐adj > 0.05). Our results establish two SNPs, rs17465637 in MIA3 and rs599839 near SORT1 as significant risk factors for MI in the American Genebank Caucasian population.
Background: Many health policy experts have endorsed insurance competition as a way to reduce the cost and improve the quality of medical care. In line with this approach, health insurance exchanges, ...such as HealthCare.gov, allow consumers to compare insurance plans online. Since the 2013 rollout of HealthCare.gov, administrators have added features intended to help consumers better understand and compare insurance plans. Although well-intentioned, changes to exchange websites affect the context in which consumers view plans, or choice architecture, which may impede their ability to choose plans that best fit their needs at the lowest cost. Methods: By simulating the 2016 HealthCare.gov enrollment experience in an online sample of 374 American adults, we examined comprehension and choice of HealthCare.gov plans under its choice architecture. Results: We found room for improvement in plan comprehension, with higher rates of misunderstanding among participants with poor math skills (P < 0.05). We observed substantial variations in plan choice when identical plan sets were displayed in different orders (P < 0.001). However, regardless of order in which they viewed the plans, participants cited the same factors as most important to their choices (P > 0.9). Limitations: Participants were drawn from a general population sample. The study does not assess for all possible plan choice influencers, such as provider networks, brand recognition, or help from others. Conclusions: Our findings suggest two areas of improvement for exchanges: first, the remaining gap in consumer plan comprehension and, second, the apparent influence of sorting order—and likely other choice architecture elements—on plan choice. Our findings inform strategies for exchange administrators to help consumers understand and select plans that better fit their needs.
Background: Many health policy experts have endorsed insurance competition as a way to reduce the cost and improve the quality of medical care. In line with this approach, health insurance exchanges, ...such as HealthCare.gov , allow consumers to compare insurance plans online. Since the 2013 rollout of HealthCare.gov , administrators have added features intended to help consumers better understand and compare insurance plans. Although well-intentioned, changes to exchange websites affect the context in which consumers view plans, or choice architecture, which may impede their ability to choose plans that best fit their needs at the lowest cost. Methods: By simulating the 2016 HealthCare.gov enrollment experience in an online sample of 374 American adults, we examined comprehension and choice of HealthCare.gov plans under its choice architecture. Results: We found room for improvement in plan comprehension, with higher rates of misunderstanding among participants with poor math skills ( P < 0.05). We observed substantial variations in plan choice when identical plan sets were displayed in different orders ( P < 0.001). However, regardless of order in which they viewed the plans, participants cited the same factors as most important to their choices ( P > 0.9). Limitations: Participants were drawn from a general population sample. The study does not assess for all possible plan choice influencers, such as provider networks, brand recognition, or help from others. Conclusions: Our findings suggest two areas of improvement for exchanges: first, the remaining gap in consumer plan comprehension and, second, the apparent influence of sorting order—and likely other choice architecture elements—on plan choice. Our findings inform strategies for exchange administrators to help consumers understand and select plans that better fit their needs.
Potassium disorders are one of the most common electrolyte abnormalities in patients with chronic kidney disease (CKD), contributing to poor clinical outcomes. Maintaining serum potassium levels ...within the physiologically normal range is critically important in these patients. Dietary potassium restriction has long been considered a core strategy for the management of chronic hyperkalemia in patients with CKD. However, this has been challenged by recent evidence suggesting a paradigm shift toward fostering more liberalized, plant-based dietary patterns. The advent of novel potassium binders and an improved understanding of gastrointestinal processes involved in potassium homeostasis (e.g., gastrointestinal potassium wasting) may facilitate a paradigm shift and incorporation of heart-healthy potassium-enriched food sources. Nevertheless, uncertainty regarding the risk-benefit of plant-based diets in the context of potassium management in CKD remains, requiring well-designed clinical trials to determine the efficacy of dietary potassium manipulation toward improvement of clinical outcomes in patients with CKD.
How cell metabolism regulates DNA repair is incompletely understood. Here, we define a GTP-mediated signaling cascade that links metabolism to DNA repair and has significant therapeutic implications. ...GTP, but not other nucleotides, regulates the activity of Rac1, a guanine nucleotide-binding protein, which promotes the dephosphorylation of serine 323 on Abl-interactor 1 (Abi-1) by protein phosphatase 5 (PP5). Dephosphorylated Abi-1, a protein previously not known to activate DNA repair, promotes nonhomologous end joining. In patients and mouse models of glioblastoma, Rac1 and dephosphorylated Abi-1 mediate DNA repair and resistance to standard-of-care genotoxic treatments. The GTP-Rac1-PP5-Abi-1 signaling axis is not limited to brain cancer, as GTP supplementation promotes DNA repair and Abi-1-S323 dephosphorylation in nonmalignant cells and protects mouse tissues from genotoxic insult. This unexpected ability of GTP to regulate DNA repair independently of deoxynucleotide pools has important implications for normal physiology and cancer treatment.
A newly described GTP-dependent signaling axis is an unexpected link between nucleotide metabolism and DNA repair. Disrupting this pathway can overcome cancer resistance to genotoxic therapy while augmenting it can mitigate genotoxic injury of normal tissues. This article is featured in Selected Articles from This Issue, p. 5.
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