miR-96 inhibits cardiac hypertrophy by targeting growth factor receptor-bound 2

Sun

et al. 2021

Front. Cell Dev. Biol.

Cardiorenal syndrome type 3 (CRS-3) is damage to the heart following acute kidney injury (AKI). Although many experiments have found that inflammation, oxidative stress, and cardiomyocyte death are involved in cardiomyocyte pathophysiological alterations during CRS-3, they lack a non-bias analysis to figure out the primary mediator of cardiac dysfunction. Herein proteomic analysis was operated in CRS-3 and growth factor receptor-bound protein 2 (Grb2) was identified as a regulator involving AKI-related myocardial damage. Increased Grb2 was associated with cardiac diastolic dysfunction and mitochondrial bioenergetics impairment; these pathological changes could be reversed through the administration of a Grb2-specific inhibitor during AKI. Molecular investigation illustrated that augmented Grb2 promoted cardiomyocyte mitochondrial metabolism disorder through inhibiting the Akt/mTOR signaling pathway. Besides that, Mouse Inflammation Array Q1 further identified IL-6 as the upstream stimulator of Grb2 upregulation after AKI. Exogenous administration of IL-6 induced cardiomyocyte damage and mitochondrial bioenergetics impairment, whereas these effects were nullified in cardiomyocytes pretreated with Grb2 inhibitor. Our results altogether identify CRS-3 to be caused by the upregulations of IL-6/Grb2 which contribute to cardiac dysfunction through inhibiting the Akt/mTOR signaling pathway and inducing cardiomyocyte mitochondrial bioenergetics impairment. This finding provides a potential target for the clinical treatment of patients with CRS-3.

Section: Introductionsupporting

confidence: 90%

Grb2 Induces Cardiorenal Syndrome Type 3: Roles of IL-6, Cardiomyocyte Bioenergetics, and Akt/mTOR Pathway

Sun

et al. 2021

Front. Cell Dev. Biol.

“…PLSR analysis gave quantitative outputs to how likely each microRNA was involved in our response. Certain microRNA’s identified by our anaylsis have been shown to regulate important function like fibrosis (miR-27a and miR-29c 26, 27 ), cardiac hypertrophy (miR-29c 28 , miR-96 29, 30 , miR-182 31, 32 and miR-185 33 ), angiogenesis (miR-27a 34 ), and apoptotsis (miR-138 35, 36 , miR-25 37 ). Although, our model is predictive of microRNA-based mechanism, these targets still need to be validated in the future studies.…”

Section: Discussionmentioning

confidence: 93%

Experimental, Systems, and Computational Approaches to Understanding the MicroRNA-Mediated Reparative Potential of Cardiac Progenitor Cell–Derived Exosomes From Pediatric Patients

Agarwal

George

Bhutani

et al. 2017

Circulation Research

145

153

Rationale Studies have demonstrated that exosomes can repair cardiac tissue post myocardial infarction (MI) and recapitulate the benefits of cellular therapy. Objective We evaluated the role of donor age and hypoxia of human pediatric cardiac progenitor cell (CPC)-derived exosomes, in a rat model of ischemia reperfusion (IR) injury. Methods and Results Human CPCs from the right atrial appendages from children of different ages undergoing cardiac surgery for congenital heart defects were isolated and cultured under hypoxic or normoxic conditions. Exosomes were isolated from the culture-conditioned media and delivered to athymic rats following IR injury. Echocardiography at day-3 post-MI suggested statistically improved function in neonatal hypoxic and neonatal normoxic groups compared to saline-treated controls. At 28 days post-MI exosomes derived from neonatal normoxia, neonatal hypoxia, infant hypoxia, and child hypoxia significantly improved cardiac function compared to saline-treated controls. Staining showed decreased fibrosis and improved angiogenesis in hypoxic groups compared to controls. Finally, using sequencing data, a computational model was generated to link microRNA levels to specific outcomes. Conclusion CPC exosomes derived from neonates improved cardiac function independent of culture oxygen levels, while CPC-exosomes from older children were not reparative unless subjected to hypoxic conditions. Cardiac functional improvements were associated with increased angiogenesis, reduced fibrosis and improved hypertrophy resulting in improved cardiac function; however, mechanisms for normoxic neonatal CPC exosomes improved function independent of those mechanisms. This is the first study of its kind demonstrating that donor age and oxygen content in the microenvironment significantly alter the efficacy of human CPC-derived exosomes.

“…Nevertheless, the role of miR-96-5p in cardiac remodeling is controversial. Some studies maintained that overexpression of miR-96-5p leads to the apoptosis and fibrosis of cardiomyocytes following myocardial infarction (49,50), whereas other investigations suggested the antipyroptotic and antihypertrophic properties of miR-96-5p by targeting NLR pyrin domain containing 3 and growth factor receptor-bound 2 (51,52). IP3R is a key regulator of SBP and contractility of VSMCs (53).…”

Section: Discussionmentioning

confidence: 99%

Cebpd Regulates Oxidative Stress and Inflammatory Responses in Hypertensive Cardiac Remodeling

Zhao,

Hu,

Zhang

et al. 2023

Shock

Hypertension seems to inevitably cause cardiac remodeling, increasing the mortality of patients. This study aimed to explore the molecular mechanism of CCAAT enhancer binding protein delta (CEBPD)-mediated oxidative stress and inflammation in hypertensive cardiac remodeling. The hypertensive murine model was established through angiotensin-II (Ang II) injection and hypertensive mice underwent overexpressed CEBPD vector injection, cardiac function evaluation and observation of histological changes. The cell model was established by Ang II treatment and transfected with overexpressed CEBPD vector. Cell viability and surface area, oxidative stress [reactive oxygen species (ROS)/superoxide dismutase (SOD)/ superoxide dismutase (LDH)/MDA) were assessed and inflammatory factors (TNF-α/IL-1β/IL-6/IL-10) were determined both in vivo and in vitro. The levels of CEBPD, miR-96-5p, inositol 1,4,5-trisphosphate receptor 1 (IP3R), natriuretic peptide B, and natriuretic peptide A, collagen I, and collagen III in tissues and cells were determined. The binding relationships of CEBPD/miR-96-5p/IP3R 3’UTR were validated. CEBPD was reduced in cardiac tissue of hypertensive mice and CEBPD upregulation improved cardiac function and attenuated fibrosis and hypertrophy, along with reductions of ROS/LDH/MDA/TNF-α/IL-1β/IL-6 and increases in SOD/IL-10. CEBPD enriched on the miR-96-5p promoter to promote miR-96-5p expression, while CEBPD and miR-96-5p negatively regulated IP3R. miR-96-5p silencing/IP3R overexpression reversed the alleviative role of CEBPD overexpression in hypertensive mice. In summary, CEBPD promoted miR-96-5p to negatively regulate IP3R expression to inhibit oxidative stress and inflammation, thereby alleviating hypertensive cardiac remodeling.