RESUMEN
ABSTRACT: Cardiovascular diseases (CVDs) are the foremost cause of morbidity and mortality worldwide. Current clinical interventions include invasive approaches for progressed conditions and pharmacological assistance for initial stages, which has systemic side effects. Preventive, curative, diagnostic, and theranostic (therapeutic + diagnostic) approaches till date are not very useful in combating the ongoing CVD epidemic, which demands a promising efficient alternative approach. To combat the growing CVD outbreak globally, the ideal strategy is to make the therapeutic intervention least invasive and direct to the heart to reduce the bystander effects on other organs and increase the bioavailability of the therapeutics to the myocardium. The application of nanoscience and nanoparticle-mediated approaches have gained a lot of momentum because of their efficient passive and active myocardium targeting capability owing to their improved specificity and controlled release. This review provides extensive insight into the various types of nanoparticles available for CVDs, their mechanisms of targeting (eg, direct or indirect), and the utmost need for further development of bench-to-bedside cardiac tissue-based nanomedicines. Furthermore, the review aims to summarize the different ideas and methods of nanoparticle-mediated therapeutic approaches to the myocardium till date with present clinical trials and future perspectives. This review also reflects the potential of such nanoparticle-mediated tissue-targeted therapies to contribute to the sustainable development goals of good health and well-being.
Asunto(s)
Enfermedades Cardiovasculares , Cardiopatías , Humanos , Miocardio , Cardiopatías/diagnóstico , Cardiopatías/tratamiento farmacológico , Nanomedicina , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , CorazónRESUMEN
Pathological cardiac hypertrophy is associated with ventricular fibrosis leading to heart failure. The use of thiazolidinediones as Peroxisome Proliferator-Activated Receptor-gamma (PPARγ)-modulating anti-hypertrophic therapeutics has been restricted due to major side-effects. The present study aims to evaluate the anti-fibrotic potential of a novel PPARγ agonist, deoxyelephantopin (DEP) in cardiac hypertrophy. AngiotensinII treatment in vitro and renal artery ligation in vivo were performed to mimic pressure overload-induced cardiac hypertrophy. Myocardial fibrosis was evaluated by Masson's trichrome staining and hydroxyproline assay. Our results showed that DEP treatment significantly improves the echocardiographic parameters by ameliorating ventricular fibrosis without any bystander damage to other major organs. Following molecular docking, all-atomistic molecular dynamics simulation, reverse transcription-polymerase chain reaction and immunoblot analyses, we established DEP as a PPARγ agonist stably interacting with the ligand-binding domain of PPARγ. DEP specifically downregulated the Signal Transducer and Activator of Transcription (STAT)-3-mediated collagen gene expression in a PPARγ-dependent manner, as confirmed by PPARγ silencing and site-directed mutagenesis of DEP-interacting PPARγ residues. Although DEP impaired STAT-3 activation, it did not have any effect on the upstream Interleukin (IL)-6 level implying possible crosstalk of the IL-6/STAT-3 axis with other signaling mediators. Mechanistically, DEP increased the binding of PPARγ with Protein Kinase C-delta (PKCδ) which impeded the membrane translocation and activation of PKCδ, downregulating STAT-3 phosphorylation and resultant fibrosis. This study, therefore, for the first time demonstrates DEP as a novel cardioprotective PPARγ agonist. The therapeutic potential of DEP as an anti-fibrotic remedy can be exploited against hypertrophic heart failure in the future.