multilevel-microdissection-functional-structural-profiling-human

Multilevel Microdissection and Functional-Structural Profiling of Human Renal Arterial Branches

Renal vascular dysfunction plays a critical role in the pathogenesis of multiple clinical conditions, including acute kidney injury, renal ischemia, and ...

renal-artery-function-histopathology-linked-to-plasma-fecal

Renal Artery Function and Histopathology Linked to Plasma and Fecal Metabolites in Heart Failure Patients

The gut microbiota and its associated host-microbe co-metabolites are increasingly recognized as key regulators of systemic metabolic balance and the ...

Peking University

Beijing Key Laboratory of Cardiovascular Receptors Research

Haihe Laboratory of Cell Ecosystem

Excessive death of cardiac myocytes leads to many cardiac diseases, including myocardial infarction, arrhythmia, heart failure and sudden cardiac death. For the last several decades, most work on cell death has focused on apoptosis, which is generally considered as the only form of regulated cell death, whereas necrosis has been regarded to be an unregulated process. Recent findings reveal that necrosis also occurs in a regulated manner and that it is closely related to the physiology and pathophysiology of many organs, including the heart. The recognition of necrosis as a regulated process mandates a re-examination of cell death in the heart together with the mechanisms and therapy of cardiac diseases. In this study, we summarize the regulatory mechanisms of the programmed necrosis of cardiomyocytes, that is, the intrinsic (mitochondrial) and extrinsic (death receptor) pathways. Furthermore, the role of this programmed necrosis in various heart diseases is also delineated. Finally, we describe the currently known pharmacological inhibitors of several of the key regulatory molecules of regulated cell necrosis and the opportunities for their therapeutic use in cardiac disease. We intend to systemically summarize the recent progresses in the regulation and pathological significance of programmed cardiomyocyte necrosis along with its potential therapeutic applications to cardiac diseases. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.

Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond.

Heart failure is a syndrome in which the heart cannot pump enough blood to meet the body's needs, resulting from impaired ventricular filling or ejection of blood. Heart failure is still a global public health problem and remains a substantial unmet medical need. Therefore, it is crucial to identify new therapeutic targets for heart failure. Ca/calmodulin-dependent kinase II (CaMKII) is a serine/threonine protein kinase that modulates various cardiac diseases. CaMKII-δ9 is the most abundant CaMKII-δ splice variant in the human heart and acts as a central mediator of DNA damage and cell death in cardiomyocytes. Here, we proved that CaMKII-δ9 mediated cardiomyocyte death promotes cardiomyopathy and heart failure. However, CaMKII-δ9 did not directly regulate cardiac hypertrophy. Furthermore, we also showed that CaMKII-δ9 induced cell death in adult cardiomyocytes through impairing the UBE2T/DNA repair signaling. Finally, we demonstrated no gender difference in the expression of CaMKII-δ9 in the hearts, together with its related cardiac pathology. These findings deepen our understanding of the role of CaMKII-δ9 in cardiac pathology and provide new insights into the mechanisms and therapy of heart failure.

CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure.

CaMKII (Ca/calmodulin-dependent kinase II) plays a central role in cardiac ischemia/reperfusion (I/R) injury-an important therapeutic target for ischemic heart disease. In the heart, CaMKII-δ is the predominant isoform and further alternatively spliced into 11 variants. In humans, CaMKII-δ9 and CaMKII-δ3, the major cardiac splice variants, inversely regulate cardiomyocyte viability with the former pro-death and the latter pro-survival. However, it is unknown whether specific inhibition of the detrimental CaMKII-δ9 prevents cardiac I/R injury and, if so, what is the underlying mechanism. Here, we aim to investigate the cardioprotective effect of specific CaMKII-δ9 inhibition against myocardial I/R damage and determine the underlying mechanisms.

Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation.

Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease, the leading cause of morbidity and mortality worldwide. At present, there is no effective therapy for reducing cardiac I/R injury. CaMKII (Ca/calmodulin-dependent kinase II) plays a pivotal role in the pathogenesis of severe heart conditions, including I/R injury. Pharmacological inhibition of CaMKII is an important strategy in the protection against myocardial damage and cardiac diseases. To date, there is no drug targeting CaMKII for the clinical therapy of heart disease. Furthermore, at present, there is no selective inhibitor of CaMKII-δ, the major CaMKII isoform in the heart.

Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth.

Myocardial infarction and revascularization cause cardiac ischemia/reperfusion (I/R) injury featuring cardiomyocyte death and inflammation. The Ca/calmodulin dependent protein kinase II (CaMKII) family are serine/ threonine protein kinases that are involved in I/R injury. CaMKII exists in four different isoforms, α, β, γ, and δ. In the heart, CaMKII-δ is the predominant isoform，with multiple splicing variants, such as δB, δC and δ9. During I/R, elevated intracellular Ca concentrations and reactive oxygen species activate CaMKII. In this review, we summarized the regulation and function of CaMKII in multiple cell types including cardiomyocytes, endothelial cells, and macrophages during I/R. We conclude that CaMKII mediates inflammation in the microenvironment of the myocardium, resulting in cell dysfunction, elevated inflammation, and cell death. However, different CaMKII-δ variants exhibit distinct or even opposite functions. Therefore, reagents/approaches that selectively target specific CaMKII isoforms and variants are needed for evaluating and counteracting the exact role of CaMKII in I/R injury and developing effective treatments against I/R injury.

CaMKII, 'jack of all trades' in inflammation during cardiac ischemia/reperfusion injury.

Apelin is a key hormone in cardiovascular homeostasis that activates the apelin receptor (APLNR), which is regarded as a promising therapeutic target for cardiovascular disease. However, adverse effects through the β-arrestin pathway limit its pharmacological use. Here, we report cryoelectron microscopy (cryo-EM) structures of APLNR-G complexes bound to three agonists with divergent signaling profiles. Combined with functional assays, we have identified "twin hotspots" in APLNR as key determinants for signaling bias, guiding the rational design of two exclusive G-protein-biased agonists WN353 and WN561. Cryo-EM structures of WN353- and WN561-stimulated APLNR-G protein complexes further confirm that the designed ligands adopt the desired poses. Pathophysiological experiments have provided evidence that WN561 demonstrates superior therapeutic effects against cardiac hypertrophy and reduced adverse effects compared with the established APLNR agonists. In summary, our designed APLNR modulator may facilitate the development of next-generation cardiovascular medications.

Structure-based design of non-hypertrophic apelin receptor modulator.

Cardiac ischemia/reperfusion (I/R) injury has emerged as an important therapeutic target for ischemic heart disease. Currently, there is no effective therapy for reducing cardiac I/R injury. Damage-associated molecular patterns are endogenous molecules released after cellular damage to exaggerate tissue inflammation and injury. RIPK3 (receptor-interacting protein kinase 3), a well-established intracellular mediator of cell necroptosis and inflammation, serves as a circulating biomarker of multiple diseases. However, whether extracellular RIPK3 also exerts biological functions in cardiac I/R injury remains totally unknown.

Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury.

Harnessing the power of structure-based design: A new lease on life for cardiovascular drug development with apelin receptor modulators.

Septic cardiomyopathy (SCM), a severe complication in sepsis, significantly increases the mortality of septic patients. Ferroptosis, an iron-regulated cell death, has been implicated in the development of SCM. Wogonin, a flavonoid from the root of the skullcap, exhibits anti-inflammatory, anti-allergic, and anti-apoptotic activities. In this study, we investigated the effects of wogonin on SCM and associated cardiomyocyte ferroptosis. Cecal ligation and puncture (CLP) surgery was performed in mice to establish a SCM model. Wogonin (20, 40 and 60 mg·kg, i.p.) was administered 2 h prior to CLP surgery. We showed that wogonin pretreatment dose-dependently mitigated CLP-induced cardiac dysfunction, myocardial damage, and deranged cardiomyocyte contractility. Furthermore, wogonin pretreatment ameliorated cardiac inflammation, oxidative stress, and mitochondrial dysfunction in CLP-challenged mice. We demonstrated that wogonin exerted the cardioprotective effects through suppressing cardiomyocyte ferroptosis both in vivo and in vitro. We revealed that wogonin directly bound to and inhibited ALOX15 (arachidonic acid 15-lipoxygenase), a lipoxygenase that governed the oxidation of polyunsaturated fatty acids to initiate ferroptosis. Pharmacological inhibition of ALOX15 using a specific inhibitor ML351 (10 mg·kg·d, i.p. for 7 days prior to CLP surgery) markedly diminished cardiac abnormalities and cardiomyocyte ferroptosis in CLP-challenged mice. In LPS-challenged HL-1 cardiomyocytes, overexpression of ALOX15 or supplement of its downstream metabolite 15-HpETE (1 μM) diminished the anti-ferroptotic effects of wogonin. Our results demonstrate that wogonin protects against SCM through inhibition of ALOX15-meditated ferroptosis.

Wogonin attenuates septic cardiomyopathy by suppressing ALOX15-mediated ferroptosis.

Myocardial ischemia/reperfusion (I/R) injury is a substantial challenge to the management of ischemic heart disease, the leading cause of mortality worldwide. Arachidonic acid (AA) is a prominent polyunsaturated fatty acid in the human body and plays an important role in various physiological and pathological conditions. AA metabolic enzymes determine AA levels; however, currently there is no comprehensive analysis of AA enzymes in cardiac I/R injury.

Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury.

Viral myocarditis, an inflammatory heart disorder caused by viral infections, often leads to poor outcomes due to the lack of effective prevention and treatment strategies. Despite the characteristic feature of cardiomyocyte death in this condition, the underlying mechanisms and potential therapeutic approaches remain poorly understood. Traditional Chinese medicine (TCM), despite its extensive history in treating various diseases, has not yet been approved for the treatment of viral myocarditis. Here, we screened six TCM patent injections recommended by clinical practice guidelines for treating cardiovascular diseases and discovered that Danhong Injection (DHI) markedly reduced cardiomyocyte death induced by Coxsackievirus B3 (CVB3). Additionally, in a CVB3-infected mouse model of viral myocarditis, DHI treatment notably alleviated cardiomyocyte death (including apoptosis, necroptosis and pyroptosis), as well as inflammation, cardiac dysfunction, and mortality. Mechanistically, DHI exerted its protective effects by inhibiting CaMKII through its active monomer Dihydrotanshinone I (Dih-I), identified as a CaMKII inhibitor. In viral myocarditis patients, CaMKII phosphorylation was upregulated in the hearts. The anti-inflammatory properties and CaMKII inhibition effects of DHI were further validated in primary human peripheral blood mononuclear cells. Our findings not only demonstrate the central role of CaMKII-mediated cardiomyocyte death in the progression of viral myocarditis, but also highlight DHI as a promising therapeutic intervention for managing viral myocarditis-induced cardiac injury and related pathological response.

ArticleTotal : 2	Year
Publication title	2025
Publication title	2025

Article	Year
Programmed necrosis in cardiomyocytes: mitochondria, death receptors and beyond. British journal of pharmacology\| PubMed ID: 29774530	2019
CaMKII-δ9 Induces Cardiomyocyte Death to Promote Cardiomyopathy and Heart Failure. Frontiers in cardiovascular medicine\| PubMed ID: 35127874	2021
Targeting CaMKII-δ9 Ameliorates Cardiac Ischemia/Reperfusion Injury by Inhibiting Myocardial Inflammation. Circulation research\| PubMed ID: 35152717	2022
Novel CaMKII-δ Inhibitor Hesperadin Exerts Dual Functions to Ameliorate Cardiac Ischemia/Reperfusion Injury and Inhibit Tumor Growth. Circulation\| PubMed ID: 35317609	2022
CaMKII, 'jack of all trades' in inflammation during cardiac ischemia/reperfusion injury. Journal of molecular and cellular cardiology\| PubMed ID: 37813179	2023
Structure-based design of non-hypertrophic apelin receptor modulator. Cell\| PubMed ID: 38428423	2024
Extracellular RIPK3 Acts as a Damage-Associated Molecular Pattern to Exaggerate Cardiac Ischemia/Reperfusion Injury. Circulation\| PubMed ID: 39411860	2024
Harnessing the power of structure-based design: A new lease on life for cardiovascular drug development with apelin receptor modulators. Clinical and translational medicine\| PubMed ID: 39648165	2024
Wogonin attenuates septic cardiomyopathy by suppressing ALOX15-mediated ferroptosis. Acta pharmacologica Sinica\| PubMed ID: 40205009	2025
Intracellular L-PGDS-Derived 15d-PGJ2 Inhibits CaMKII Through Lipoxidation to Alleviate Cardiac Ischemia/Reperfusion Injury. Circulation\| PubMed ID: 40396239	2025
Danhong Injection targets CaMKII through Dihydrotanshinone I to alleviate cardiomyocyte death and inflammation in viral myocarditis. Science China. Life sciences\| PubMed ID: 40889047	2025

Junxia Zhang

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