👤 Michael S Dodd

Lipoprotein (a) (Lp[a]) is an independent risk factor for cardiovascular disease (CVD). Structurally like low-density lipoprotein, Lp(a) is distinguished by the covalent attachment of apolipoprotein(a) to apolipoprotein B-100. Although its physiological role remains incompletely understood, evidence suggests that Lp(a) may facilitate wound healing and inhibit cancer growth and metastasis. In contrast, Lp(a) exhibits proatherogenic properties; it transports proinflammatory oxidized phospholipids, induces the secretion of proinflammatory cytokines, increases endothelial permeability, promotes smooth muscle cell migration and proliferation, and upregulates adhesion molecules that facilitate monocyte recruitment and retention. In addition, Lp(a) exerts prothrombotic activity by enhancing platelet aggregation, suppressing plasminogen activation, and inhibiting fibrinolysis. Although its clinical relevance in CVD is well established, the role of Lp(a) in peripheral arterial disease (PAD) remains unclear. This narrative review aimed to synthesize and critically examine the current evidence on the biological role of Lp(a) in PAD pathogenesis and identify knowledge gaps in PAD-specific outcomes. This review summarizes the epidemiology, pathophysiology, and management of elevated Lp(a) levels in patients with PAD and examines their association with post-treatment clinical outcomes. Elevated Lp(a) levels are associated with an increased PAD incidence and a higher risk of restenosis post-revascularization. Understanding the mechanisms by which Lp(a) contributes to PAD pathogenesis is essential for developing effective targeted therapeutic approaches and improving the identification and management of high-risk patients. Show less

In the adult retina, we have previously shown that Nogo-A was highly expressed in Müller glia. However, the role of Nogo-A in the glial cell physiology is not clear. In this study, we investigated the possible influence that Nogo-A may exert on other polarized molecules in Müller cells, in particular inwardly rectifying potassium channel 4.1 (Kir4.1) and aquaporin 4 (AQP4) that respectively control potassium and water exchange in glial cells. Our results showed that adenovirus-mediated Nogo-A overexpression with AdNogo-A increased the immunofluorescent signal of Kir4.1 in rat Müller cell line 1 (rMC-1) cells but did not change its expression level by Western blotting. In vivo, AdNogo-A induced ectopic Kir4.1 immunoreactivity throughout the radial processes of Müller cells compared with AdLacZ control virus. Surprisingly, AdNogo-A did not modify the distribution of Dp71 and AQP4 that are common binding partners for Kir4.1 in the dystrophin-associated protein (DAP) complex anchored at the plasma membrane of Müller glia. Immunoprecipitation experiments revealed molecular interactions between Nogo-A and Kir4.1. In Nogo-A KO mouse retinae, the distribution of Kir4.1 was not different from that observed in Wild-Type (WT) animals. In addition, potassium conductance did not change in freshly dissociated Nogo-A KO Müller glia compared with WT cells. In summary, the increase of Nogo-A expression can selectively influence the distribution of Kir4.1 in glia but is not essential for Kir4.1-mediated potassium conductance at the plasma membrane in physiological conditions. Nogo-A-Kir4.1 interactions may, however, contribute to pathological processes taking place in the retina, for instance, after ischemia. Show less

Energy depletion has been highlighted as an important contributor to the pathology of hypertrophic cardiomyopathy (HCM), a common inherited cardiac disease. Pharmacological reversal of energy depletion appears an attractive approach and the use of perhexiline has been proposed as it is thought to shift myocardial metabolism from fatty acid to glucose utilisation, increasing ATP production and myocardial efficiency. We used the Mybpc3-targeted knock-in mouse model of HCM to investigate changes in the cardiac metabolome following perhexiline treatment. Echocardiography indicated that perhexiline induced partial improvement of some, but not all hypertrophic parameters after six weeks. Non-targeted metabolomics, applying ultra-high performance liquid chromatography-mass spectrometry, described a phenotypic modification of the cardiac metabolome with 272 unique metabolites showing a statistically significant change (p < 0.05). Changes in fatty acids and acyl carnitines indicate altered fatty acid transport into mitochondria, implying reduction in fatty acid beta-oxidation. Increased glucose utilisation is indirectly implied through changes in the glycolytic, glycerol, pentose phosphate, tricarboxylic acid and pantothenate pathways. Depleted reduced glutathione and increased production of NADPH suggest reduction in oxidative stress. These data delineate the metabolic changes occurring during improvement of the HCM phenotype and indicate the requirements for further targeted interventions. Show less