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Ubiquitination plays a vital role in controlling vascular inflammation, cellular protein quality control, and minimizing misfolded protein toxicity. Pellino-1 (Peli1), a type of E3 ubiquitin ligase, has emerged as a critical regulator of the innate immune response; however, its role in the repair and regeneration of ischemic myocardium remains to be elucidated. Mice (8-12 weeks old, male and females) were divided into (i) Wild type (ii) cardiomyocyte-specific Peli1 overexpressed (AMPEL1Tg/+), (iii) cardiomyocyte-specific Peli1 knockout (CP1KO) and were subjected to sham and left anterior descending artery ligation. The tissues were collected at various time points after surgery for Western blot, and immunohistochemical analyses. Echocardiography is performed 30 days after myocardial infarction. Cardiomyocytes isolated from wild-type, Peli1 overexpressed and knockout mice were used to study the interaction between cardiomyocytes and endothelial cells in vitro under oxidative stress and cells were used for Western blot, flow cytometric analysis, and scratch assay. We observed faster wound closure and increased expression of angiogenic factors with MCECs treated with conditioned media obtained from the AMPEL1Tg/+ cardiomyocytes compared to CPIKO and WT cardiomyocytes. Again, AMPEL1Tg/+MI mice showed preserved systolic function and reduced fibrosis compared to the CPIKOMI and WTMI groups. Capillary and arteriolar density were found to be increased in AMPEL1Tg/+MI compared to CP1KOMI. Increased survival and angiogenic factors such as p-Akt, p-MK2, p-IkBα, VEGF, cIAP2, and Bcl2 were observed in AMPEL1Tg/+ compared to CP1KO and WT mice subjected to MI. The present study uncovers the crucial role of cardiac Peli1 as a regulator of the repair and regeneration of ischemic myocardium by using multiple genetically engineered mouse models. [Display omitted] • Peli1 deletion worsen cardiac function after myocardial infarction. • Cardiomyocytes rich with Peli1 triggers angiogenic signal in ischemic heart. • Clear cross-talk between Peli1 overexpressed cardiomyocytes and endothelial cells. • Peli1 regulated pro-and anti-apoptotic molecules under oxidative stress. [ABSTRACT FROM AUTHOR]