TGF-β: The Molecular Mechanisms of Atherosclerosis - insights into SMAD Pathways and Gene Therapy Prospects

Abstract: Atherosclerosis, a leading cause of global morbidity and mortality, is characterized by plaque formation resulting from the accumulation of fibrous elements, lipids, and calcification in arteries, leading to complications such as ischemic stroke, coronary artery disease, and myocardial infarction. Traditional treatments primarily address symptoms but fail to target underlying causes, prompting exploration of novel approaches like gene therapy. The TGF-β family, encompassing TGF-β1, TGF-β2, and TGF-β3, plays a critical role in cellular processes including proliferation, apoptosis, and migration, with its dysregulation strongly linked to cardiovascular diseases. In atherosclerosis, TGF-β influences key factors, such as macrophage cholesterol regulation, plaque stability, and vascular smooth muscle cell function, while also contributing to endothelial dysfunction— an early stage in disease development. Personalized medicine has highlighted the importance of tailoring therapies to genetic profiles, particularly regarding TGF-β pathway variations such as SNPs in TGF-β1 and TGFBR2, which could inform more precise interventions. Emerging technologies like CRISPR-Cas9 and RNA-based therapies enable targeted modulation of these genetic factors, offering new avenues to mitigate disease progression. CRISPR-Cas9 allows direct editing of gene loci linked to atherosclerosis, potentially correcting mutations or modulating expression levels, while RNA-based therapies, including siRNAs and antisense oligonucleotides, provide additional precision tools for addressing dysregulated genes. This review focuses on identifying key genes and additional molecular players involved in or regulated by the TGF-β pathway that may serve as precise targets for gene therapy intervention in atherosclerosis and related cardiovascular diseases. By targeting genes involved in cholesterol metabolism, inflammation, and endothelial function, gene therapy offers a targeted strategy to ameliorate the genetic drivers of these conditions. In summary, modulation of TGF-β signaling by gene therapy has the potential to revolutionize the treatment of atherosclerosis and other cardiovascular diseases while shedding light on the underlying genetic mechanisms of these disorders.