Our data suggest that cardiac remodeling associated with HCM determines a significant release of miRNAs into the bloodstream: the circulating levels of both cardiac- and non-cardiac-specific miRNAs are significantly increased in the plasma of HCM patients. However, correlation with left ventricular hypertrophy parameters holds true for only a few miRNAs (i.e., miR-199a-5p, -27a, and -29a), whereas only miR-29a is significantly associated with both hypertrophy and fibrosis, identifying it as a potential biomarker for myocardial remodeling assessment in HCM.
Extracellular vesicles (EVs) are a heterogeneous group of natural particles with relevance for the treatment of cardiovascular diseases. The endogenous properties of these vesicles allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be engineered to enhance their stability, bioactivity, presentation and capacity for on target binding at both cell type and tissue levels. The therapeutic potential of native (i.e., EVs that were not modified via donor cell or direct modulation) and engineered (i.e. EVs that were modified either pre-or post-isolation or whose pharmacokinetics/presentation was altered using engineering methodologies EVs is still limitedly explored in the context of cardiovascular diseases. Efforts to tap into the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of molecular compound delivery. In this review, we outline the endogenous properties of EVs that make them natural delivery agents as well as those features that can be improved using bioengineering approaches. We also discuss the therapeutic applications of native and engineered EVs for cardiovascular applications and examine the opportunities and challenges that need to be addressed to advance this research area with an emphasis on clinical translation. Key points• EVs secreted from stem/progenitor cells as well as differentiated somatic cells have regenerative properties in the context of myocardial infarction, ischemic limb, chronic wounds and stroke.
Heavy metal hyperaccumulation in plants is an intriguing and poorly understood phenomenon. Transmembrane metal transporters are assumed to play a key role in this process. We describe the cloning and isolation of three zinc transporter cDNAs from the Zn hyperaccumulator Thlaspi caerulescens. The ZTP1 gene is highly similar to the Arabidopsis ZAT gene. Of the other two, one is most probably an allele of the recently cloned ZNT1 gene from T. caerulescens (Pence et al; Proceedings of the National Academy of Science USA 97, 4956–4960, 2000). The second, called ZNT2, is a close homologue of ZNT1. All three zinc transporter genes show increased expression in T. caerulescens compared with the non‐hyperaccumulator congener T. arvense, suggesting an important role in heavy metal hyperaccumulation. ZNT1 and ZNT2 are predominantly expressed in roots and ZTP1 is mainly expressed in leaves but also in roots. In T. arvense, ZNT1 and ZNT2 are exclusively expressed under conditions of Zn deficiency. Their expression in T. caerulescens is barely Zn‐responsive, suggesting that Zn hyperaccumulation might rely on a decreased Zn‐induced transcriptional downregulation of these genes. ZTP1 expression was higher in plants from calamine soil than in plants from serpentine or normal soil. The calamine plants were also the most Zn tolerant, suggesting that high ZTP1 expression might contribute to Zn tolerance.
Heavy metal hyperaccumulation in plants is an intriguing and poorly understood phenomenon. Transmembrane metal transporters are assumed to play a key role in this process. We describe the cloning and isolation of three zinc transporter cDNAs from the Zn hyperaccumulator Thlaspi caerulescens. The ZTP1 gene is highly similar to the Arabidopsis ZAT gene. Of the other two, one is most probably an allele of the recently cloned ZNT1 gene from T. caerulescens (Pence et al; Proceedings of the National Academy of Science USA 97, 4956-4960, 2000). The second, called ZNT2, is a close homologue of ZNT1. All three zinc transporter genes show increased expression in T. caerulescens compared with the non-hyperaccumulator congener T. arvense, suggesting an important role in heavy metal hyperaccumulation. ZNT1 and ZNT2 are predominantly expressed in roots and ZTP1 is mainly expressed in leaves but also in roots. In T. arvense, ZNT1 and ZNT2 are exclusively expressed under conditions of Zn deficiency. Their expression in T. caerulescens is barely Zn-responsive, suggesting that Zn hyperaccumulation might rely on a decreased Zn-induced transcriptional downregulation of these genes. ZTP1 expression was higher in plants from calamine soil than in plants from serpentine or normal soil. The calamine plants were also the most Zn tolerant, suggesting that high ZTP1 expression might contribute to Zn tolerance.
Inflammation contributes to renal ischemia reperfusion (I/R) injury, potentially causing renal dysfunction. The inflammatory infiltrate mainly consists of neutrophils, which are deleterious for the renal tissue. Because CD44 is expressed by neutrophils and is rapidly upregulated by capillary endothelial cells after I/R injury, it was hypothesized that CD44 might play an important role in the development of I/R injury. This study showed that rapid CD44 upregulation on renal capillary endothelial cells mediates neutrophil recruitment to the postischemic tissue. Hence, CD44 deficiency led to decreased influx of neutrophils regardless of comparable levels in chemotactic factors expressed in the kidney. The reduced influx of neutrophils was associated with preserved renal function and morphology. Adoptive transfer experiments of labeled neutrophils revealed that endothelial CD44 rather than neutrophil CD44 mediates neutrophil migration. Activation of neutrophils increased cell-surface expression of hyaluronic acid (HA). Altogether, a novel mechanism in the recruitment of neutrophils that involves interaction of endothelial CD44 and neutrophil HA was found. Either blocking endothelial CD44 or removal of neutrophil HA decreased rolling and adhesion of neutrophils. Administration of anti-CD44 to mice reduced the influx of neutrophils into the postischemic tissue, associated with renal function preservation. Therefore, anti-CD44 -based therapies may contribute to prevent or reduce renal I/R injury.
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