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

Salvage of Extensively Scarred Hands: Wide Awake Tenolysis and Interpositional Free Tissue Transfer.

Background This study introduced a dedicated technical approach to extensive hand adhesions, combined with failed primary nerve reconstruction. Wide awakelocal anesthesia no tourniquet (WALANT) tenolysis and interpositional free tissue transfer forge the main facets of the proposed reconstructive strategy. Methods A prospective study was conducted, including 22 patients diagnosed with extensive tendon adhesions in addition to failed primary nerve repair. After wide awake tenolysis, 20 adipofascial radial forearm flaps and two ALT flaps were used to wrap the tendons, whereas the nerves were grafted after complete separation from the tendons. Nerve recovery; final total range of motion of the fingers; and the disabilities of the arm, shoulder, and hand score were recorded in detail. Results All flaps healed uneventfully. Final assessment of the median nerve revealed M3 or more motor power and S3 sensory recovery in all patients except one patient who attained no muscle power at all and S1 as regards the sensory assessment. The ulnar nerve evaluation revealed that two of five patients did not recover motor power at all (M0), and the remaining three patients recovered M3 motor power with variable sensory outcomes. Final assessment of total range of motion of the fingers and the DASH score showed a statistically significant improvement except for one patient. Conclusion WALANT tenolysis and interposition of well-vascularized fascial flaps along with simultaneous nerve grafts in extensively scarred hands provided goodfunctional outcomes

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

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

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

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

In a cardiomyocyte hypertrophy model with aberrant Wnt activation, proteomic analysis of extracellular vesicles and transcriptomic profiling reveal a proteostasis signature for early patho-physiological states of cardiomyocytes