Dataset Information

SGLT1: A Potential Drug Target for Cardiovascular Disease.

ABSTRACT: SGLT1 and SGLT2 are the two main members of the sodium-glucose cotransporters (SGLTs), which are mainly responsible for glucose reabsorption in the body. In recent years, many large clinical trials have shown that SGLT2 inhibitors have cardiovascular protection for diabetic and non-diabetic patients independent of lowering blood glucose. However, SGLT2 was barely detected in the hearts of humans and animals, while SGLT1 was highly expressed in myocardium. As SGLT2 inhibitors also have a moderate inhibitory effect on SGLT1, the cardiovascular protection of SGLT2 inhibitors may be due to SGLT1 inhibition. SGLT1 expression is associated with pathological processes such as cardiac oxidative stress, inflammation, fibrosis, and cell apoptosis, as well as mitochondrial dysfunction. The purpose of this review is to summarize the protective effects of SGLT1 inhibition on hearts in various cell types, including cardiomyocytes, endothelial cells, and fibroblasts in preclinical studies, and to highlight the underlying molecular mechanisms of protection against cardiovascular diseases. Selective SGLT1 inhibitors could be considered a class of drugs for cardiac-specific therapy in the future.

SUBMITTER: Zhao M

PROVIDER: S-EPMC10332373 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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SGLT1: A Potential Drug Target for Cardiovascular Disease.

Zhao Mengnan M Li Na N Zhou Hong H

Drug design, development and therapy 20230706

SGLT1 and SGLT2 are the two main members of the sodium-glucose cotransporters (SGLTs), which are mainly responsible for glucose reabsorption in the body. In recent years, many large clinical trials have shown that SGLT2 inhibitors have cardiovascular protection for diabetic and non-diabetic patients independent of lowering blood glucose. However, SGLT2 was barely detected in the hearts of humans and animals, while SGLT1 was highly expressed in myocardium. As SGLT2 inhibitors also have a moderate ...[more]

PMID: 37435096

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Project description:Background: Hepatic knockdown of the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene or the angiopoietin-like 3 (ANGPTL3) gene has been demonstrated to reduce blood low-density lipoprotein cholesterol (LDL-C) levels, and hepatic knockdown of the angiotensinogen (AGT) gene has been demonstrated to reduce blood pressure. Genome editing can productively target each of these three genes in hepatocytes in the liver, offering the possibility of durable “one-and-done” therapies for hypercholesterolemia and hypertension. However, concerns around making permanent gene sequence changes via DNA strand breaks might hinder acceptance of these therapies. Epigenome editing offers an alternative approach to gene inactivation, via silencing of gene expression by methylation of the promoter region, but the long-term durability of epigenome editing remains to be established. Objectives and Results: We assessed the ability of epigenome editing to durably reduce the expression of the human PCSK9, ANGPTL3, and AGT genes in HuH-7 hepatoma cells. Cells treated with the CRISPRoff epigenome editor and PCSK9 guide RNAs were maintained for up to 124 cell doublings and demonstrated durable knockdown of gene expression and increased CpG dinucleotide methylation in the promoter, exon 1, and intron 1 regions. In contrast, cells treated with CRISPRoff and ANGPTL3 guide RNAs experienced only transient knockdown of gene expression. Cells treated with CRISPRoff and AGT guide RNAs also experienced transient knockdown of gene expression; although initially there was increased CpG methylation throughout the early part of the gene, this methylation was geographically heterogeneous—transient in the promoter, and stable in intron 1.Conclusions: This work demonstrates precise and durable gene regulation via methylation, supporting a new therapeutic approach for protection against cardiovascular disease via knockdown of genes such as PCSK9. However, the durability of knockdown with methylation changes is not generalizable across target genes, likely limiting the therapeutic potential of epigenome editing compared to other modalities.

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SGLT1: A Potential Drug Target for Cardiovascular Disease.

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SGLT1: A Potential Drug Target for Cardiovascular Disease.

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