Introduction: Ischemic heart disease (IHD) is characterized by reduced blood supply to the myocardium and is aggravated by Type 2 Diabetes Mellitus (T2DM). Most of the RNA produced by the human genome is “non-coding” in potential and involved in regulatory processes. These include circular RNAs (circRNAs) and microRNAs (miRNAs). miRNAs bind to the 3’UTR region of their target genes and repress their expression post-transcriptionally. CircRNAs lack free ends which gives them increased stability and makes them good candidates for diagnostic biomarkers and therapeutic interventions. CircRNAs bind miRNAs via a process called “sponging” that prevents the miRNAs from binding to their target genes. This study investigates the regulatory role of circRNAs in IHD and its effect on endothelial cell (EC) function. Methods and Results: We have generated bulk RNA-seq data on whole transcriptome and small RNA using heart left ventricle (LV) biopsies of 3 groups of cardiac surgery patients: 1) and 2) suffering from IHD) with/without T2DM and 3) non-ischemic controls. Bioinformatics analysis of this data has identified significant differentially expressed circRNAs, miRNAs, and mRNAs in IHD and IHD + T2DM patients. Using available databases and tools, we have predicted “sponging associations” between circRNAs and miRNAs as well as targets of sponged miRNAs producing circRNA-miRNA-mRNA networks. Since fundamental changes in IHD include a decline in EC function, we extracted all components of the networks expressed in ECs. Of note is circNPHP1, which is upregulated in IHD + T2DM patients and in human microvascular endothelial cells (HMVECs) under hypoxic and hypoxic + high glucose (HG) conditions. Furthermore, knockdown of circNPHP1 in HMVECs leads to a significant reduction of proliferation and angiogenesis under hypoxic and hypoxic + HG conditions. The downstream miRNA and mRNA connections of circNPHP1 are currently under investigation. Conclusion: circNPHP1 expression shows concordance in clinical samples and cultured cells in response to perturbation (ischemia/hypoxia and T2DM/HG). It also seems to be playing a role in EC function restoration under these conditions and is therefore promising for further investigation into its therapeutic target potential.