The mammalian heart has long been considered to be a postmitotic organ. It was thought that, in the postnatal period, the heart underwent a transition from hyperplasic growth (more cells) to hypertrophic growth (larger cells) due to the conversion of cardiomyocytes from a proliferative state to one of terminal differentiation. This hypothesis was gradually disproven, as data were published showing that the myocardium is a more dynamic tissue in which cardiomyocyte karyokinesis and cytokinesis produce new cells, leading to the hyperplasic regeneration of some of the muscle mass lost in various pathological processes. microRNAs have been shown to be critical regulators of cardiomyocyte differentiation and proliferation and may offer the novel opportunity of regenerative hyperplasic therapy. Here we summarize the relevant processes and recent progress regarding the functions of specific microRNAs in cardiac development and regeneration.
The concept of gene therapy was introduced in the 1970s after the development of recombinant DNA technology. Despite the initial great expectations, this field experienced early setbacks. Recent years have seen a revival of clinical programs of gene therapy in different fields of medicine. There are many promising targets for genetic therapy as an adjunct to cardiac surgery. The first positive long-term results were published for adenoviral administration of vascular endothelial growth factor with coronary artery bypass grafting. In this review we analyze the past, present, and future of gene therapy in cardiac surgery. The articles discussed were collected through PubMed and from author experience. The clinical trials referenced were found through the Wiley clinical trial database (http://www.wiley.com/legacy/wileychi/genmed/clinical/) as well as the National Institutes of Health clinical trial database (Clinicaltrials.gov).
The S100A1 gene is a promising target enhancing contractility and survival post myocardial infarction (MI). Achieving sufficient gene delivery within safety limits is a major translational problem. This proof of concept study evaluates viral-mediated S100A1 overexpression featuring a novel liquid jet delivery (LJ) method. 24 rats after successful MI were divided into 3 groups (n=8 ea.): saline control (SA), ssAAV9.S100A1 (SS) delivery, and scAAV9.S100A1 (SC) delivery (both 1.2×1011 viral particles). For each post MI rat, the LJ device fired three separate 100 μL injections into the myocardium. Following 10 weeks, all rats were evaluated with echocardiography, quantitative polymerase chain reaction (qPCR), and overall S100A1 and CD38 immune protein. At 10 weeks all groups demonstrated a functional decline from baseline, but the S100A1 therapy groups displayed preserved LV function with significantly higher ejection fraction %; SS group [60±3] and SC group [57±4] versus saline [46±3], p<0.05. Heart qPCR testing showed robust S100A1 in the SS [10,147±3993] and SC [35,155±5808] copies per 100 ng DNA, while off target liver detection was lower in both SS [40±40], SC [34,841±3164] respectively. Cardiac S100A1 protein expression was [4.3±0.2] and [6.1±0.3] fold higher than controls in the SS and SC groups respectively, p<0.05.
Objective Heart failure is accompanied by upregulation of transforming growth factor beta signaling, accumulation of collagen and dysregulation of sarcoplasmic reticulum calcium ATPase cardiac isoform 2a (SERCA2a). We examined the fibrotic response in small and large myocardial infarct and the effect of overexpressing the SERCA2a gene. Methods Ischemic cardiomyopathy was induced via creation of large infarct or small infarct in 26 sheep. All animals were divided into four groups: small infarct; large infarct with heart failure; gene treated (large infarct with heart failure followed by AAV1.SERCA2a gene construct transfer by molecular cardiac surgery with recirculating delivery); and control group. Results Heart failure was significantly less pronounced in the gene treated and small infarct groups than in the large infarct group. Expression of transforming growth factor beta signaling components was significantly higher in large infarct compared to small infarct or gene treated. Further, both the angiotensin II type 1 receptor and angiotensin II were significantly elevated in small and large infarcts, while gene treatment diminished this effect. Active fibrosis with de novo collagen synthesis was evident in large infarct, while small infarct and gene treatment groups showed less fibrosis with a lower ratio of de novo to mature collagen. Conclusions The data presented supports that the progression of fibrosis is mediated through increased transforming growth factor beta and angiotensin II signaling, which is mitigated by increased SERCA2a gene expression.
Pathogenesis of heart diseases is associated with an altered expression profile of hundreds of genes. miRNAs are a newly identified layer of gene regulation operating at the post-transcriptional level by pairing to complementary base sequences in target mRNAs. Genetic data have identified the roles of miRNAs in basic pathological processes associated with heart failure: apoptosis, fibrosis, myocardial hypertrophy and cardiac remodeling. Many reports demonstrated that aberrantly expressed miRNAs and their modulation have effects on cardiac insufficiency. Here, we overview the advances in miRNAs as potential targets in the modulation of the heart failure phenotype. miRNA-based therapy holds great promise as a future strategy for treating heart diseases and identifying emerging signaling pathways responsible for the progression of heart failure.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.