Improving Cardiac Microenvironment as a Novel Strategy against Diabetic Ischemic Heart Failure - PROJECT SUMMARY Type 2 diabetes leads to greater morbidity and mortality of ischemic heart failure (IHF) with incompletely understood mechanisms. Recent studies show that diabetes reduces the effectiveness of treatments that work in nondiabetics, leading to a `universal resistance' condition that worsens IHF. However, advancements in cellular secretome research highlight the crucial role of the local microenvironment in influencing disease progression and treatment efficacy. This proposal aims to leverage these insights to transform treatment strategies for individuals with diabetic IHF. Cardiac secretomes, known as “cardiokines”, are crucial in maintaining a healthy cardiac microenvironment. C1q/tumor necrosis factor-related protein-9 (CTRP9), a new identified cardiokine, is a potent cardioprotective molecule that is significantly downregulated in diabetic animals and patients. Our research indicated that CTRP9 reduction resulted in failed cell therapy interventions for diabetic IHF, while the therapy succeeded in nondiabetic patients. Small extracellular vesicles (sEVs) are key mediators in cardioprotection during cell therapy. However, how diabetic downregulation of CTRP9 may adversely impact sEV properties and hinder its cardioprotection in the diabetic population remains unexplored. Seeking an engineered approach to modify sEV to effectively overcome the challenges of rescuing the compromised microenvironment in diabetic IHF is our goal. Our data showed that adipose-derived stromal cells (ADSC) serves as favarable implantable parent bioresources produces potent sEV. Genetic engineering to overexpress N- cadherin (Ncad), the receptor of CTRP9, in ADSC (termed NOE-ADSC) significantly enhances their cardioprotective effects. Currently there is a lack of efficient methods to increase sEV surface protein. It is worth noting that our approach demonstrated that CTRP9 stimulates the surface adiponectin level on sEV derived from parent NOE-ADSC. Hence, we poisted a novel hypothesis that “Diabetic downregulated CTRP9 and its receptor impairs sEV production and diminishes cardioprotection, while administering CTRP9 to enhance sEV generation from NOE-ADSC, which serve as parent bioresources suprior to sEV alone, represent a novel intervention against diabetic IHF, providing synergistic protection through CTRP9 and adiponectin. To test this novel hypothesis, we will complete 3 specific aims. Aim 1 will provide in vivo evidence that bioengineered sEV is the causative factor responsible for NOE-ADSC cardioprotection against IHF. Aim 2 will prove that cardionyocyte-generated CTRP9 is essential for NOE-ADSC sEV production and cardioprotection, diabetic downregulation of CTRP9 is causatively related to the incapability of sEV production and resistance to the therapy effect in the diabetic heart. Aim 3 will illustrate the underlying mechanisms that sEV surface adiponectin (APN) is responsible for NOE-ADSC-sEV cardioprotection, and the administration of bioengineered sEV parent bioresources NOE-ADSC may be a novel strategy against diabetic IHF. Therefore, this study will reveal a novel mechanism for the diabetic IHF and identify new therapies (sEV bioengineering modification) against post-MI remodeling in diabetic patients.
