Carnosinylation of Cardiac Antigens Attenuates Immunogenic Responses and Improves Function in Failing Hearts.

Objective: To investigate the effects of carnosine on heart failure and to examine whether this is associated with reduced immunogenicity of oxidatively-generated aldehyde modified proteins.

Background: Heart failure is associated with the accumulation of lipid derived aldehydes that form immunogenic protein adducts. However, the pathological impact of these aldehydes and aldehyde-modified proteins in heart failure has not been assessed.

Exercise sensitizes the pressure diuresis response: shifting immune landscapes may underlie renal adaptations.

Physical activity and exercise confer health benefits through actions on several physiological systems; however, the mechanisms by which they impact renal health remain poorly understood. Studies show that exercise slows age-related decline in kidney function and protects against acute kidney injury (AKI). We hypothesize that exercise triggers adaptative responses, which preserve hemodynamic balance in the kidneys under stress.

Cell Function Graphics: TOGGLE delineates fate and function within individual cell types via single-cell transcriptomics.

Functional RNA plays a crucial role in regulating cellular processes throughout the life cycle of a cell. Identifying functional changes at each stage, from inception to development to maturation, functional execution, and eventual death or pathological transformation, often requires systematic comparisons of functional expression across cell populations. However, because cells of the same type often exhibit similar gene expression patterns regardless of function or fate, it is challenging to distinguish the stages of cellular fate or functional states within the same cell type, which also limits our understanding of cellular memory.

Neutrophil-secreted CHI3L1 exacerbates cardiac dysfunction and inflammation after myocardial infarction.

Myocardial infarction (MI) triggers acute inflammation, marked by neutrophil infiltration. Although neutrophils are central to this response, the exact role of various neutrophil-derived factors is not fully understood. Clinical studies have linked one such enigmatic factor, chitinase-3 like-1, to MI outcomes.

Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity. Calcium is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. Here we show a robust pathway for new calcium signaling-based cardiac regenerative strategies.

Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways.

Matricellular protein CCN1 promotes collagen alignment and scar integrity after myocardial infarction.

Background: Members of the cellular communication network family (CCN) of matricellular proteins, like CCN1, have long been implicated in the regulation of cellular processes underlying wound healing, tissue fibrogenesis, and collagen dynamics. While many studies suggest antifibrotic actions for CCN1 in the adult heart through the promotion of myofibroblast senescence, they largely relied on exogenous supplementation strategies in in vivo models of cardiac injury where its expression is already induced-which may confound interpretation of its function in this process. The objective of this study was to interrogate the role of the endogenous protein on fibroblast function, collagen structural dynamics, and its associated impact on cardiac fibrosis after myocardial infarction (MI).

Kv beta complex facilitates exercise-induced augmentation of myocardial perfusion and cardiac growth.

The oxygen sensitivity of voltage-gated potassium (Kv) channels regulates cardiovascular physiology. Members of the Kv1 family interact with intracellular Kvβ proteins, which exhibit aldo-keto reductase (AKR) activity and confer redox sensitivity to Kv channel gating. The Kvβ proteins contribute to vasoregulation by controlling outward K currents in smooth muscle upon changes in tissue oxygen consumption and demand.

Pharmacological or genetic inhibition of LTCC promotes cardiomyocyte proliferation through inhibition of calcineurin activity.

Cardiomyocytes (CMs) lost during ischemic cardiac injury cannot be replaced due to their limited proliferative capacity, which leads to progressive heart failure. Calcium (Ca) is an important signal transducer that regulates key cellular processes, but its role in regulating CM proliferation is incompletely understood. A drug screen targeting proteins involved in CM calcium cycling in human embryonic stem cell-derived cardiac organoids (hCOs) revealed that only the inhibition of L-Type Calcium Channel (LTCC), but not other Ca regulatory proteins (SERCA or RYR), induced the CM cell cycle.

PU.1 inhibition does not attenuate cardiac function deterioration or fibrosis in a murine model of myocardial infarction.

Activated cardiac fibroblasts are involved in both reparative wound healing and maladaptive cardiac fibrosis after myocardial infarction (MI). Recent evidence suggests that PU.1 inhibition can enable reprogramming of profibrotic fibroblasts to quiescent fibroblasts, leading to attenuation of pathologic fibrosis in several fibrosis models.

Transient Cell Cycle Induction in Cardiomyocytes to Treat Subacute Ischemic Heart Failure.

Background: The regenerative capacity of the heart after myocardial infarction is limited. Our previous study showed that ectopic introduction of 4 cell cycle factors (4F; CDK1 [cyclin-dependent kinase 1], CDK4 [cyclin-dependent kinase 4], CCNB [cyclin B1], and CCND [cyclin D1]) promotes cardiomyocyte proliferation in 15% to 20% of infected cardiomyocytes in vitro and in vivo and improves cardiac function after myocardial infarction in mice.

Methods: Using temporal single-cell RNA sequencing, we aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis.

Single dose of synthetic microRNA-199a or microRNA-149 mimic does not improve cardiac function in a murine model of myocardial infarction.

Intramyocardial injection of synthetic microRNAs (miRs) has recently been reported to be beneficial after myocardial infarction (MI). We conducted a randomized blinded study to evaluate the efficacy and reproducibility of this strategy in a mouse model of reperfused MI using rigorous methodology. Mice undergoing a 60-min coronary occlusion followed by reperfusion were randomly assigned to control miR, hsa-miR-199a-3p, hsa-miR-149-3p, or hsa-miR-149-5p mimic treatment.

Cardiac Mesenchymal Cells Cultured at Physiologic Oxygen Tension Have Superior Therapeutic Efficacy in Heart Failure Caused by Myocardial Infarction.

Stem/progenitor cells are usually cultured at atmospheric O tension (21%); however, since physiologic O tension in the heart is ∼5%, using 21% O may cause oxidative stress and toxicity. Cardiac mesenchymal cells (CMCs), a newly discovered and promising type of progenitor cells, are effective in improving left ventricle (LV) function after myocardial infarction (MI). We have previously shown that, compared with 21% O, culture at 5% O increases CMC proliferation, telomerase activity, telomere length, and resistance to severe hypoxia .

Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy.

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 10 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 10 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 10 cells each) can be fully replicated by a single combined dose of 3 × 10 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 10) and vehicle × 2; or (3) three doses of CPCs (1 × 10 each).

Echocardiography-guided percutaneous left ventricular intracavitary injection as a cell delivery approach in infarcted mice.

In the field of cell therapy for heart disease, a new paradigm of repeated dosing of cells has recently emerged. However, the lack of a repeatable cell delivery method in preclinical studies in rodents is a major obstacle to investigating this paradigm. We have established and standardized a method of echocardiography-guided percutaneous left ventricular intracavitary injection (echo-guided LV injection) as a cell delivery approach in infarcted mice.

Comparison of One and Three Intraventricular Injections of Cardiac Progenitor Cells in a Murine Model of Chronic Ischemic Cardiomyopathy.

Repeated doses of c-kit cardiac progenitor cells (CPCs) are superior to a single dose in improving LV function in rats with old myocardial infarction (MI). However, this concept needs testing in different species to determine whether it is generalizable. We used a new murine model of chronic ischemic cardiomyopathy whose unique feature is that cell therapy was started late (3 months) after MI.

Cardiac mesenchymal cells from failing and nonfailing hearts limit ventricular dilation when administered late after infarction.

Although cell therapy-mediated cardiac repair offers promise for treatment/management of heart failure, lack of fundamental understanding of how cell therapy works limits its translational potential. In particular, whether reparative cells from failing hearts differ from cells derived from nonfailing hearts remains unexplored. Here, we assessed differences between cardiac mesenchymal cells (CMC) derived from failing (HF) versus nonfailing (Sham) hearts and whether the source of donor cells (i.

Inducible cardiac-specific overexpression of cyclooxygenase-2 (COX-2) confers resistance to ischemia/reperfusion injury.

The role of cyclooxygenase-2 (COX-2) in cardiovascular biology remains controversial. Although COX-2 has been reported to mediate the protective actions of late preconditioning, other studies show that it is also an important mediator of inflammation, toxic shock, and apoptosis, resulting in significant dysfunction and injury in several tissues. To determine whether increased myocardial COX-2, in itself, is protective, cardiac-specific, inducible (Tet-off) COX-2 transgenic (iCOX-2 TG) mice were generated by crossbreeding α-MyHC-tTA transgenic mice (tetracycline transactivator [tTA]) with CMV/TRE-COX-2 transgenic mice.

Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair.

Although cell therapy improves cardiac function after myocardial infarction, highly variable results and limited understanding of the underlying mechanisms preclude its clinical translation. Because many heart failure patients are diabetic, we examined how diabetic conditions affect the characteristics of cardiac mesenchymal cells (CMC) and their ability to promote myocardial repair in mice. To examine how diabetes affects CMC function, we isolated CMCs from non-diabetic C57BL/6J (CMC) or diabetic B6.

Astragalus Granule Prevents Ca Current Remodeling in Heart Failure by the Downregulation of CaMKII.

Background: was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from , shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca current () in HF mice by the downregulation of Ca/calmodulin-dependent protein kinase II (CaMKII).

Myocardial Reparative Properties of Cardiac Mesenchymal Cells Isolated on the Basis of Adherence.

Background: The authors previously reported that the c-kit-positive (c-kit) cells isolated from slowly adhering (SA) but not from rapidly adhering (RA) fractions of cardiac mesenchymal cells (CMCs) are effective in preserving left ventricular (LV) function after myocardial infarction (MI).

Objectives: This study evaluated whether adherence to plastic alone, without c-kit sorting, was sufficient to isolate reparative CMCs.

Methods: RA and SA CMCs were isolated from mouse hearts, expanded in vitro, characterized, and evaluated for therapeutic efficacy in mice subjected to MI.

Repeated doses of cardiac mesenchymal cells are therapeutically superior to a single dose in mice with old myocardial infarction.

We have recently demonstrated that repeated administrations of c-kit cardiac progenitor cells (CPCs) have cumulative beneficial effects in rats with old myocardial infarction (MI), resulting in markedly greater improvement in left ventricular (LV) function compared with a single administration. To determine whether this paradigm applies to other species and cell types, mice with a 3-week-old MI received one or three doses of cardiac mesenchymal cells (CMCs), a novel cell type that we have recently described. CMCs or vehicle were infused percutaneously into the LV cavity, 14 days apart.

Preconditioning Human Cardiac Stem Cells with an HO-1 Inducer Exerts Beneficial Effects After Cell Transplantation in the Infarcted Murine Heart.

The regenerative potential of c-kit(+) cardiac stem cells (CSCs) is severely limited by the poor survival of cells after transplantation in the infarcted heart. We have previously demonstrated that preconditioning human CSCs (hCSCs) with the heme oxygenase-1 inducer, cobalt protoporphyrin (CoPP), has significant cytoprotective effects in vitro. Here, we examined whether preconditioning hCSCs with CoPP enhances CSC survival and improves cardiac function after transplantation in a model of myocardial infarction induced by a 45-minute coronary occlusion and 35-day reperfusion in immunodeficient mice.