Research Background
Study Overview
Ischemic heart disease (IHD) restricts blood supply to the myocardium and can compromise endothelial function, microvascular perfusion, and tissue repair. Type 2 diabetes mellitus (T2DM) can further aggravate vascular dysfunction, increasing the need for complementary strategies that support cardiac angiogenesis and endothelial recovery.
Circular RNAs (circRNAs) are a class of noncoding RNAs that can influence gene regulation by interacting with microRNAs (miRNAs). By binding and sequestering specific miRNAs—a process often described as miRNA sponging—circRNAs may alter the expression of downstream messenger RNA (mRNA) targets. However, these interconnected regulatory networks remain incompletely characterized in the human ischemic heart, particularly in the presence of T2DM.
A study published in JACC: Basic to Translational Science investigated circRNA–miRNA–mRNA networks in human left ventricular tissue and functionally examined the leading candidate network in endothelial cells. The research aimed to identify regulatory mechanisms with potential relevance to microvascular repair in IHD and diabetes.
Study Design
From Human Cardiac Tissue to Functional Validation
The researchers analyzed RNA sequencing data from left ventricular biopsies collected during cardiac surgery. The final analysis included three clinical groups: patients with IHD, patients with both IHD and T2DM, and non-IHD controls. Whole-transcriptome and small-RNA sequencing data were used to profile circRNAs, mRNAs, and miRNAs across these groups.
Differentially expressed RNAs were integrated with predicted circRNA–miRNA and miRNA–mRNA interactions to construct regulatory networks. The researchers then prioritized subnetworks whose components were expressed in endothelial cells and associated with pathways relevant to endothelial function and angiogenesis.
Leading candidates were examined in cultured endothelial cells exposed to hypoxia or combined hypoxia and high-glucose conditions. CircRNA pulldown, targeted silencing, miRNA inhibition and overexpression, gene expression measurements, and endothelial cell assays were used to test the proposed molecular interactions and their functional consequences.
Research Highlights
Key Findings
Distinct RNA Networks Characterize Ischemic and Diabetic Hearts
The integrated analysis revealed different circRNA–miRNA–mRNA interaction patterns across the IHD, IHD with T2DM, and non-IHD groups. These disease-associated networks provided a framework for identifying regulatory relationships that may influence endothelial responses in the ischemic myocardium.
Among the prioritized candidates, circNPHP1 emerged as the central component of a putative proangiogenic subnetwork. Its expression pattern in human tissue and in endothelial cells exposed to disease-mimicking conditions supported further functional investigation.
circNPHP1 Supports Endothelial Angiogenic Activity
Silencing circNPHP1 in endothelial cells reduced angiogenic activity and cell proliferation under hypoxic and hypoxic high-glucose conditions. These experiments showed that circNPHP1 is not only associated with the disease-related transcriptomic network but also contributes functionally to endothelial behavior.
The results identify circNPHP1 as a positive regulator of the cellular processes required for vascular growth and repair under conditions designed to model ischemia and diabetes.
A circNPHP1–miR-221-3p–VEGFA/BCL2 Axis Regulates Angiogenesis
CircRNA pulldown experiments confirmed an interaction between circNPHP1 and miR-221-3p. Reducing circNPHP1 expression also decreased the expression of the miR-221-3p target genes VEGFA and BCL2, both of which are relevant to endothelial survival and angiogenic function.
Experiments combining circNPHP1 silencing with miR-221-3p inhibition or overexpression further supported the proposed sponging mechanism. Together, the findings define a regulatory axis through which circNPHP1 helps maintain proangiogenic gene expression in endothelial cells.
Research Significance
Implications for Therapeutic Angiogenesis Research
By connecting transcriptomic patterns in human left ventricular tissue with mechanistic experiments in endothelial cells, this study provides a detailed view of how different classes of coding and noncoding RNA may cooperate in the ischemic heart. It also highlights the value of integrated circRNA, miRNA, and mRNA analysis for moving from candidate discovery to functional validation.
The circNPHP1–miR-221-3p–VEGFA/BCL2 network offers a potential direction for research into therapies that promote microvascular repair in IHD, including disease complicated by T2DM. However, circNPHP1 remains a research-stage candidate. Further in vivo studies, delivery strategies, safety assessment, and clinical validation will be needed before its therapeutic potential can be established.
BMKGENE Contribution
Supporting Transcriptomic Network Discovery
BMKGENE provided transcriptome sequencing and bioinformatics analysis services for this study. These services supported the generation and comparative analysis of the RNA datasets used to investigate disease-associated expression patterns and construct circRNA–miRNA–mRNA regulatory networks.
The resulting transcriptomic evidence helped the researchers prioritize candidate interactions for downstream mechanistic and functional validation in endothelial cells.
Transcriptome Sequencing · Bioinformatics Analysis
Original Publication
Anwar, M., Sarkar, M., Ford, K., et al. Human Left Ventricle circRNA-miRNA-mRNA Network Analyses Reveal a Novel Proangiogenic Role for circNPHP1 Under Ischemic Conditions. JACC: Basic to Translational Science 11(2), 101468 (2026). DOI: 10.1016/j.jacbts.2025.101468.
Post time: Sep-04-2026
