Abstract Cardiovascular diseases are the most common cause of death worldwide and Myocardial Infarction (MI) is the primary symptom of cardiovascular disease. In MI, Damage-Associated Molecular Patterns (DAMPs) released by dying cells play an important role in driving the inflammatory response following myocardial damage with potentially adverse or pro-regenerative outcomes. Since angiogenesis is a key process to ameliorate the sequelae of MI and the effect of DAMPs on cardiac cells are still widely unknown, hereby we present a novel model to study how DAMPs affect the gene expression of human Cardiac Microvascular Endothelial Cells (CMECs), one of the most abundant cell types in the heart, aiming to identify lncRNA targets to induce regenerative angiogenesis in patients with MI. To generate a cocktail of DAMPs, cells were isolated from the heart tissue of patients undergoing septal myectomy via collagenase treatment and exposed to repeated cycles of freeze-thawing to induce cell rupture. The release of endogenous molecules (DAMPs), such as DNA, was confirmed by nano drop. CMECs were then stimulated with DAMPs for 24h and RNA sequencing was performed. Finally, to predict potential co-regulation between lncRNAs and angiogenic proteins, a combination of PLAIDOH and NoRCE were used. The RNA sequencing revealed a total of 1294 Differently Expressed Genes (DEGs) in CMECs stimulated with DAMPs, of which 218 were lncRNAs annotated in GENCODE v42. Among the top 50 DEGs were found proteins involved in cell growth, proliferation, and immune response such as FGF5, CEP128, and IL32 and the GSE analysis revealed that proliferation (mitosis), migration, and angiogenesis were among the most enriched terms. The analysis with PLAIDOH and NoRCe revealed ∼25 differentially expressed lncRNAs which correlate with proteins involved in cell cycle and mitotic entry (Pearson 0.6-0.99 and p-value < 0.05). Among these were found HIF1A-AS3, TGFB-OT1, TGFB-AS1. Following the in-silico analysis, results were confirmed by qPCR. qPCR for HIFA1A-AS3 showed a significant reduction of 40% when CMECs were stimulated with DAMPs (p-value: 0.04) confirming the sequencing results. Whether HIFA1A-AS3 is involved in cell proliferation will now be validated with KO experiments. In conclusion, the administration of DAMPs to CMECs for 24h induced genes involved in proliferation, migration, and angiogenesis, processes that are also highly regulated in MI. By combining PLAIDOH and NoRCE we were able to identify lncRNAs which correlate in expression with protein-coding genes involved in these processes indicating co-regulation. These experiments recapitulate the main endothelial cell processes found in MI via administration of DAMPs and enable us to identify lncRNA targets to promote regenerative angiogenesis. Hence, this brings us one step closer to identifying gene therapy targets capable of inducing regenerative angiogenesis in patients with MI.