Macrophage-based therapeutic approaches for cardiovascular diseases.

Despite the advances in treatment options, cardiovascular disease (CVDs) remains the leading cause of death over the world. Chronic inflammatory response and irreversible fibrosis are the main underlying pathophysiological causes of progression of CVDs. In recent decades, cardiac macrophages have been recognized as main regulatory players in the development of these complex pathophysiological conditions. Numerous approaches aimed at macrophages have been devised, leading to novel prospects for therapeutic interventions. Our review covers the advancements in macrophage-centric treatment plans for various pathologic conditions and examines the potential consequences and obstacles of employing macrophage-targeted techniques in cardiac diseases.

Intercellular transfer of miR-200c-3p impairs the angiogenic capacity of cardiac endothelial cells.

As mediators of intercellular communication, extracellular vesicles containing molecular cargo, such as microRNAs, are secreted by cells and taken up by recipient cells to influence their cellular phenotype and function. Here we report that cardiac stress-induced differential microRNA content, with miR-200c-3p being one of the most enriched, in cardiomyocyte-derived extracellular vesicles mediates functional cross-talk with endothelial cells. Silencing of miR-200c-3p in mice subjected to chronic increased cardiac pressure overload resulted in attenuated hypertrophy, smaller fibrotic areas, higher capillary density, and preserved cardiac ejection fraction. We were able to maximally rescue microvascular and cardiac function with very low doses of antagomir, which specifically silences miR-200c-3p expression in non-myocyte cells. Our results reveal vesicle transfer of miR-200c-3p from cardiomyocytes to cardiac endothelial cells, underlining the importance of cardiac intercellular communication in the pathophysiology of heart failure.

Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure.

Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.

Harnessing the power of RNA therapeutics in treating ischemic heart failure: the TRAIN-HEART story.

Ischemic heart disease (IHD) is one of the world's foremost killers, accounting for 16% of all deaths worldwide. IHD is the main cause of heart failure (HF), as it leads to pathological changes in the heart, improper pumping function and eventual death. Therapeutic interventions usually follow a systemic general strategy for all heart failure subtypes due to the lack of a deep understanding of the disease mechanisms. Hence, HF and IHD therapeutics need groundbreaking concepts to guide the development of a new therapeutics class that tackles the disease at a molecular level. The TRAIN-HEART consortium, a Marie Sklodowska-Curie Actions Innovative Training Network (MSCA-ITN) funded by the European Commission, was established with the goal of filling that gap and developing RNA-based cardiovascular therapeutics. Created in the context of the Horizon 2020 research and innovation program, TRAIN-HEART comprises three key work packages (WPs) focusing on the pathogenesis of heart disease (WP1), the therapeutic potential of RNA therapeutics (WP2), and the development of new efficient delivery systems (WP3). Fifteen international early stage researchers (ESRs) from multiple complementary scientific disciplines were recruited to collaborate with a network of PIs from nine academic and eight non-academic partners in various disciplines to fully harness their collective potential for the betterment of HF treatment. This article provides an overview of the benefits of being part of an MSCA-ITN, with its different training and networking opportunities, maximizing ESRs' potential and broadening collaborative research possibilities. Finally, it describes what was like to do a PhD during the COVID-19 pandemic, with all the uncertainty and concern attached to it. Luckily, TRAIN-HEART stood out as a proactive network, finding new initiatives and alternatives to promote scientific and personal development. By bringing together leading academic teams, (biotech) companies, and highly motivated researchers, TRAIN-HEART is expanding scientific horizons and accelerating future development of effective RNA-based therapies to treat IHD.

Non-coding RNAs in cardiac inflammation: key drivers in the pathophysiology of heart failure.

Heart failure is among the most progressive diseases and a leading cause of morbidity. Despite several advances in cardiovascular therapies, pharmacological treatments are limited to relieve symptoms without curing cardiac injury. Multiple observations point to the involvement of immune cells as key drivers in the pathophysiology of heart failure. In particular, there is a growing recognition that heart failure is related to a prolonged and insufficiently repressed inflammatory response leading to molecular, cellular, and functional cardiac alterations. Over the last decades, non-coding RNAs are recognized as prominent mediators of cardiac inflammation, affecting the function of several immune cells. In the current review, we explore the contribution of the diverse immune cells in the progression of heart failure, revealing mechanistic functions for non-coding RNAs in cardiac immune cells as a new and exciting field of investigation.

Non-coding RNAs: update on mechanisms and therapeutic targets from the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart.

Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.