Human induced pluripotent stem cell-derived cardiomyocytes to study inflammation-induced aberrant calcium transient.

Heart failure with preserved ejection fraction (HFpEF) is commonly found in persons living with HIV (PLWH) even when antiretroviral therapy suppresses HIV viremia. However, studying this condition has been challenging because an appropriate animal model is not available. In this article, we studied calcium transient in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in culture to simulate the cardiomyocyte relaxation defect noted in PLWH and HFpEF and assess whether various drugs have an effect.

Intravenous Iron Repletion for Patients With Heart Failure and Iron Deficiency: JACC State-of-the-Art Review.

Iron deficiency and heart failure frequently co-occur, sparking clinical research into the role of iron repletion in this condition over the last 20 years. Although early nonrandomized studies and subsequent moderate-sized randomized controlled trials showed an improvement in symptoms and functional metrics with the use of intravenous iron, 3 recent larger trials powered to detect a difference in hard cardiovascular outcomes failed to meet their primary endpoints. Additionally, there are potential concerns related to side effects from intravenous iron, both in the short and long term.

Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske iron-sulfur protein, RISP) in hearts of adult mice.

Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings: State-of-the-Art Review.

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care.

Iron drives anabolic metabolism through active histone demethylation and mTORC1.

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway.

SIRT2 inhibition protects against cardiac hypertrophy and ischemic injury.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria, and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of () display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress.

DNA Damage and Nuclear Morphological Changes in Cardiac Hypertrophy Are Mediated by SNRK Through Actin Depolymerization.

Background: Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR).

DNA damage and nuclear morphological changes in cardiac hypertrophy are mediated by SNRK through actin depolymerization.

Background: Proper nuclear organization is critical for cardiomyocyte (CM) function, as global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy, however, the mechanism for this process is not well delineated. AMPK family of proteins regulate metabolism and DNA damage response (DDR).

The impact of underrepresented minority or marginalized identity status on training outcomes of MD-PhD students.

Dual-degree MD-PhD programs have historically lacked diversity of race, ethnicity, gender, sexual orientation, and other facets of identity. Like MD- and PhD-granting programs, MD-PhD program training environments are also marked by structural barriers that negatively impact measurable academic outcomes of underrepresented and/or marginalized students in academic medicine (racial and ethnic minority groups considered underrepresented by the National Institute of Health, sexual and gender minorities, individuals with disabilities, and individuals of low socioeconomic status). In this article, we review the existing literature on MD-PhD program disparities affecting students from these groups and provide recommendations grounded on the reviewed evidence.

Liver-specific overexpression of HKDC1 increases hepatocyte size and proliferative capacity.

A primary role of the liver is to regulate whole body glucose homeostasis. Glucokinase (GCK) is the main hexokinase (HK) expressed in hepatocytes and functions to phosphorylate the glucose that enters via GLUT transporters to become glucose-6-phosphate (G6P), which subsequently commits glucose to enter downstream anabolic and catabolic pathways. In the recent years, hexokinase domain-containing-1 (HKDC1), a novel 5th HK, has been characterized by our group and others.

Optimized protocol for quantification of mitochondrial non-heme and heme iron content in mouse tissues and cultured cells.

Impaired mitochondrial iron metabolism is associated with aging and a variety of diseases, and there is a growing need to accurately quantify mitochondrial iron levels. This protocol provides an optimized method for evaluating non-heme and heme iron in mitochondrial and cytosolic fractions of tissues and cultured cells. Our protocol consists of three steps: sample fractionation, non-heme iron measurement, and heme iron measurement.

SIRT2 inhibition protects against cardiac hypertrophy and heart failure.

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of heart failure (HF) and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of ( ) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress.

[WITHDRAWN] Hexokinase-1 mitochondrial dissociation and protein O-GlcNAcylation drive heart failure with preserved ejection fraction.

The authors have requested that this preprint be removed from Research Square.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets.

The cardiovascular system requires iron to maintain its high energy demands and metabolic activity. Iron plays a critical role in oxygen transport and storage, mitochondrial function, and enzyme activity. However, excess iron is also cardiotoxic due to its ability to catalyze the formation of reactive oxygen species and promote oxidative damage.

Ferric derisomaltose therapy and heart failure: implications and molecular insights.

Iron is essential to the production of myocardial energy and proteins critical for cardiovascular function. Nearly 50% of patients with heart failure with reduced ejection fraction (HFrEF) meet current criteria for iron deficiency, and there has been considerable interest in intravenous repletion of iron stores as a therapeutic strategy to improve HFrEF outcomes. However, the data on intravenous iron therapy in HFrEF have been mixed.

Optimized protocol to isolate primary mouse peritoneal macrophage metabolites.

Peritoneal macrophages (PMs) have been shown to have higher stability compared to other macrophage subtypes. However, obtaining enough PMs from a single mouse is often a limitation for metabolomics analysis. Here, we describe a protocol to isolate metabolites from a small number of mouse primary PMs for 13C-stable glucose tracing and metabolomics.

The molecular and metabolic landscape of iron and ferroptosis in cardiovascular disease.

The maintenance of iron homeostasis is essential for proper cardiac function. A growing body of evidence suggests that iron imbalance is the common denominator in many subtypes of cardiovascular disease. In the past 10 years, ferroptosis, an iron-dependent form of regulated cell death, has become increasingly recognized as an important process that mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischaemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia and diabetic cardiomyopathy.

ZFP36L2 suppresses mTORc1 through a P53-dependent pathway to prevent peripartum cardiomyopathy in mice.

Pregnancy is associated with substantial physiological changes of the heart, and disruptions in these processes can lead to peripartum cardiomyopathy (PPCM). The molecular processes that cause physiological and pathological changes in the heart during pregnancy are not well characterized. Here, we show that mTORc1 was activated in pregnancy to facilitate cardiac enlargement that was reversed after delivery in mice.

Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1).

Aging is associated with increased brain iron through cortex-derived hepcidin expression.

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known.