Cancers doi: 10.20517/jca.2025.51

Authors: Shouyao Zhang,Chenggui Xu,Sihan Liu,Yongli Li,Yongli Song,Xinghe Zhang

With the global trend of population aging, age-related diseases are increasing annually. The vascular system exhibits high sensitivity to aging, characterized by myocardial cell apoptosis, endothelial damage, oxidative stress, impaired autophagy, and chronic low-grade inflammatory responses. These factors significantly elevate the incidence of atherosclerosis, hypertension, myocardial infarction, and stroke, which are major cardiovascular diseases. Previous research has predominantly focused on the isolated impact of single lifestyle factors on cardiovascular aging, lacking a comprehensive framework that integrates multiple exposomes and their complex interactions. This review aims to reassess how the exposome factors, such as smoking, sedentary behavior, and the natural environment, interact and dysregulate core mechanisms such as oxidative stress and autophagy. These interactions collaboratively drive the aging of blood vessels, myocardium, and valves. We also propose targeted intervention strategies, providing insights for researchers investigating cardiovascular aging.

Cancers doi: 10.20517/jca.2025.33

Authors: Kexin Huang,Jun Ren

Proprotein convertase subtilisin/kexin type 9 (PCSK9), a crucial regulator of cholesterol metabolism, is gaining recognition for its broader involvement in aging-related disorders. Emerging evidence indicates that PCSK9 is closely linked to cardiovascular aging, neurodegenerative disorders, and metabolic dysfunction. This review synthesizes up-to-date understanding on PCSK9’s multifaceted contributions, emphasizing its role in oxidative stress, inflammation, and cellular senescence, alongside potential therapeutic implications. PCSK9 inhibition not only confers cardiovascular benefits via low-density lipoprotein-dependent and independent pathways but also exhibits broader therapeutic potential. For instance, PCSK9 inhibitors show promise in cancer immunotherapy by enhancing major histocompatibility complex class I-mediated tumor antigen presentation and in attenuating inflammation through suppressing the Toll-like receptor 4/nuclear factor kappa B pathway. However, clinical translation remains limited by tissue-specific responses and the incomplete understanding of long-term systemic effects. Overall, this review underscores the complex role of PCSK9 in the aging network and therefore highlights the need for further mechanistic studies to guide its therapeutic application.

Cancers doi: 10.20517/jca.2025.39

Authors: Yao Du,Yingying Han,Yifan Shi,Huihui Xie,Xianke Qiu,Yajun Qi,Lu He,Lintao Wang,Lina Kang,Biao Xu

Background: Heart failure is a clinical syndrome caused by underlying cardiac structural or functional impairment, leading to insufficient cardiac output and abnormally elevated intracardiac pressures in both resting and stress conditions. The stimulator of interferon genes (STING), a transmembrane protein in the endoplasmic reticulum, plays a pivotal role in initiating and sustaining chronic inflammatory responses.

Aim: We investigated whether macrophage-derived STING contributes to the pathogenesis of heart failure with preserved ejection fraction (HFpEF).

Methods and Results: Activated STING was detected in heart tissues of HFpEF mice. To study macrophage-cardiomyocyte interactions, we constructed a co-culture system of bone marrow-derived macrophages (BMDMs) and HL-1 cardiomyocytes. STING activation in BMDMs, either via a gain-of-function mutation or an agonist, promoted hypertrophy of co-cultured HL-1 cells. Mechanistically, macrophage STING activation increased Z-DNA binding protein 1 (ZBP1) expression in HL-1 cells and facilitated ZBP1-mediated inflammasome assembly.

Conclusion: These findings provide novel insight into HFpEF pathogenesis and suggest that macrophage STING may serve as a potential therapeutic target.

Cancers doi: 10.20517/jca.2025.36

Authors: Omid M. T. Rouzbehani,Marta W. Szulik,Clint Gwynn,Sophie L. Stephens,Riley W. Porter,Isidoro Cobo,Manuel Rosa-Garrido,Sarah Franklin,Sihem Boudina

Cardiovascular disease (CVD) is the leading cause of global morbidity and mortality, with epigenetic mechanisms playing a pivotal role in its pathogenesis. This review synthesizes current evidence on sex-specific epigenetic regulation in cardiac health and disease, highlighting DNA methylation, histone modifications, and non-coding RNAs as key mediators. Epigenetic processes govern cardiac development, remodeling, and responses to injury, with sex chromosomes, sex hormones, and environmental factors contributing to dimorphic patterns. Developmental programming establishes early sex biases in chromatin architecture while aging and clonal hematopoiesis amplify these differences via mutations in epigenetic modulators. Therapeutic strategies targeting epigenetic regulators hold promise but require sex-tailored approaches to optimize efficacy and minimize off-target effects. This review underscores the critical need for sex-stratified research to advance precision medicine for CVD.

Cancers doi: 10.20517/jca.2025.46

Authors: Ting Zeng,Zhongjian Zhang,Chunliu Qian,Xiaoyu Li,Shuang Li

Selective autophagy, as a crucial form of cellular autophagy, plays a vital role in the degradation of specific substances or organelles in cells. Different from traditional autophagy mechanisms, it precisely identifies and removes damaged or superfluous cellular components, such as lipids, mitochondria, or endoplasmic reticulum, thereby maintaining cellular homeostasis. In recent years, research has revealed a close relationship between selective autophagy and cardiovascular diseases (CVDs). Dysfunction in selective autophagy may promote pathological damage or disease progression in various CVDs, including atherosclerosis, heart failure, ischemic heart disease, and metabolic cardiomyopathy. In this review, we focused on summarizing the mechanisms of specific selective autophagy pathways, including lipophagy, mitophagy, and reticulophagy in CVDs. Furthermore, we analyzed the potential applications and underlying mechanisms of small-molecule compounds, which could target selective autophagy for the treatment of CVDs. We aimed to provide a new theoretical foundation for the prevention and treatment of CVDs.

Cancers doi: 10.20517/jca.2025.19

Authors: Emma R. Mehl,Ross F. Cook,Sydney M. Polson,Aykhan Yusifov,Musharraf Yusifova,Vahagn Ohanyan,Danielle R. Bruns

Background: Heart failure (HF) is a chronic disease with high morbidity and mortality among older populations. Chronic HF ultimately affects both the right (RV) and left (LV) ventricles and often presents with extra-cardiac outcomes including pulmonary hypertension (PH). Study of biventricular failure and its extra-cardiac consequences has been challenging in pre-clinical models, suggesting new models may be beneficial to uncover new mechanisms of disease. Potassium channels are implicit regulators of vascular tone and are strongly but independently associated with PH and LV dysfunction.

Aim: We hypothesized that deletion of the potassium rectifier channel Kv1.5 would cause biventricular HF, thus representing a new model from which to understand ventricle-specific mechanisms of HF.

Methods and Results: We used a model of global vasoconstriction by genetic deletion of potassium rectifier channel Kv1.5 (Kv1.5 KO). Male and female mice were studied at middle age (12-13 months) as this is when HF risk begins to increase with age. In response to Kv1.5 KO, both the LV and RV experienced elevated afterload. While Kv1.5 KO mice developed RV systolic dysfunction with hypertrophy and fibrosis, the LV developed mild hypertrophy and diastolic dysfunction. Consistent with biventricular remodeling, Kv1.5 KO mice also displayed higher liver and lung weights and exercise intolerance.

Conclusion: Deletion of Kv1.5 causes systemic and pulmonary vasoconstriction with distinct outcomes in the LV and RV. This model of biventricular dysfunction may be useful for studying extra-cardiac consequences of HF and understanding ventricle-specific mechanisms of disease.