Correction: Samak et al. Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes. Int. J. Mol. Sci. 2023, 24, 2482.

In the original publication [...].

Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes.

Cardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease.

Single-cell transcriptomics reveal extracellular vesicles secretion with a cardiomyocyte proteostasis signature during pathological remodeling.

Aberrant Wnt activation has been reported in failing cardiomyocytes. Here we present single cell transcriptome profiling of hearts with inducible cardiomyocyte-specific Wnt activation (ß-catΔex3) as well as with compensatory and failing hypertrophic remodeling. We show that functional enrichment analysis points to an involvement of extracellular vesicles (EVs) related processes in hearts of ß-catΔex3 mice. A proteomic analysis of in vivo cardiac derived EVs from ß-catΔex3 hearts has identified differentially enriched proteins involving 20 S proteasome constitutes, protein quality control (PQC), chaperones and associated cardiac proteins including α-Crystallin B (CRYAB) and sarcomeric components. The hypertrophic model confirms that cardiomyocytes reacted with an acute early transcriptional upregulation of exosome biogenesis processes and chaperones transcripts including CRYAB, which is ameliorated in advanced remodeling. Finally, human induced pluripotent stem cells (iPSC)-derived cardiomyocytes subjected to pharmacological Wnt activation recapitulated the increased expression of exosomal markers, CRYAB accumulation and increased PQC signaling. These findings reveal that secretion of EVs with a proteostasis signature contributes to early patho-physiological adaptation of cardiomyocytes, which may serve as a read-out of disease progression and can be used for monitoring cellular remodeling in vivo with a possible diagnostic and prognostic role in the future.

Micro-RNA 92a as a Therapeutic Target for Cardiac Microvascular Dysfunction in Diabetes.

Microvascular dysfunction is a pathological hallmark of diabetes, and is central to the ethology of diabetes-associated cardiac events. Herein, previous studies have highlighted the role of the vasoactive micro-RNA 92a (miR-92a) in small, as well as large, animal models. In this study, we explore the effects of miR-92a on mouse and human cardiac microvascular endothelial cells (MCMEC, HCMEC), and its underlying molecular mechanisms. Diabetic HCMEC displayed impaired angiogenesis and a pronounced inflammatory phenotype. Quantitative PCR (qPCR) showed an upregulation of miR-92a in primary diabetic HCMEC. Downregulation of miR-92a by antagomir transfection in diabetic HCMEC rescued angiogenesis and ameliorated diabetic endothelial bed inflammation. Furthermore, additional analysis of potential in silico-identified miR-92a targets in diabetic HCMEC revealed the miR-92a dependent downregulation of an essential metalloprotease, ADAM10. Accordingly, downregulation of ADAM10 impaired angiogenesis and wound healing in MCMEC. In myocardial tissue slices from diabetic pigs, ADAM10 dysregulation in micro- and macro-vasculature could be shown. Altogether, our data demonstrate the role of miR-92a in cardiac microvascular dysfunction and inflammation in diabetes. Moreover, we describe for the first time the metalloprotease ADAM10 as a novel miR-92a target, mediating its anti-angiogenic effect.

Stem Cells in Cardiovascular Medicine: Historical Overview and Future Prospects.

Cardiovascular diseases remain the leading cause of death in the developed world, accounting for more than 30% of all deaths. In a large proportion of these patients, acute myocardial infarction is usually the first manifestation, which might further progress to heart failure. In addition, the human heart displays a low regenerative capacity, leading to a loss of cardiomyocytes and persistent tissue scaring, which entails a morbid pathologic sequela. Novel therapeutic approaches are urgently needed. Stem cells, such as induced pluripotent stem cells or embryonic stem cells, exhibit great potential for cell-replacement therapy and an excellent tool for disease modeling, as well as pharmaceutical screening of novel drugs and their cardiac side effects. This review article covers not only the origin of stem cells but tries to summarize their translational potential, as well as potential risks and clinical translation.

Cardiac Hypertrophy: An Introduction to Molecular and Cellular Basis.

Ventricular hypertrophy is an ominous escalation of hemodynamically stressful conditions such as hypertension and valve disease. The pathophysiology of hypertrophy is complex and multifactorial, as it touches on several cellular and molecular systems. Understanding the molecular background of cardiac hypertrophy is essential in order to protect the myocardium from pathological remodeling, or slow down the destined progression to heart failure and cardiomyopathy. In this review we highlight the most important molecular aspects of cardiac hypertrophic growth in light of the currently available published research data.

Total Arterial Revascularization: Bypassing Antiquated Notions to Better Alternatives for Coronary Artery Disease.

Total arterial revascularization is the leading trend in coronary artery bypass grafting (CABG) for the treatment of coronary artery disease (CAD). Adding to its superiority to vein conduits, arteries allow for a high degree of versatility and long-term patency, while minimizing the need for reintervention. This is especially important for patients with multi-vessel coronary artery disease, as well as young patients. However, arterial revascularization has come a long way before being widely appreciated, with some yet unresolved debates, and advances that never cease to impress. In this review, we discuss the evolution of this surgical technique and its clinical success, as well as its most conspicuous limitations in light of accumulated published date from decades of experience.

Non-Heart-Beating Donor Heart Transplantation: Breaking the Taboo.

Roughly 60% of hearts offered for transplantation are rejected because of organ dysfunction. Moreover, hearts from circulatory-dead patients have long been thought to be non-amenable for transplantation, unlike other organs. However, tentative surgical attempts inspired by the knowledge obtained from preclinical research to recover those hearts have been performed, finally culminating in clinically successful transplants. In this review we sought to address the major concerns in non-heart-beating donor heart transplantation and highlight recently introduced developments to overcome them.

Past and Present of Total Artificial Heart Therapy: A Success Story.

The totally artificial heart (TAH) is among the most prominent medical innovations of the 21st century, especially due to the increasing population with end-stage heart failure. The progressive course of the disease, its resistance to conventional therapy, and the scarcity of hearts available for transplantation were the prime impetus for developing a TAH, especially when other options of mechanical circulatory assist devices are exhausted. In this review, we narrate the history of TAH, give an overview of its technology, and address the pros and cons of the currently available TAH models in light of published clinical experience.

Continuous-Flow Left Ventricular Assist Device Thrombosis: A Danger Foreseen is a Danger Avoided.

Left ventricular assist devices (LVAD) are an increasingly implemented therapeutic intervention for patients with end-stage heart failure. A growing body of evidence, however, has shown an elevated risk of device thrombosis, a major complication jeopardizing the patient's post-implantation survival. To date, multiple causative factors for LVAD thrombosis have been identified, such as internal shear stress, device material, infection, and inadequate anticoagulation. Understanding the mechanisms leading to LVAD thrombosis will not only enable device optimization, but also allow for better patient handling, hence improving post-implantation outcome. In this review we highlight the most commonly identified factors leading to LVAD thrombosis and discuss their mechanisms.