李冉
BACKGROUND:Cardiac-resident or -enriched microRNAs (miRNAs) could be released into the bloodstream becoming circulating cardiac miRNAs, which are increasingly recognized as non-invasive and accessible biomarkers of multiple heart diseases. However, dilated cardiomyopathy (DCM)-associated circulating miRNAs (DACMs) and their roles in DCM pathogenesis remain largely unexplored.METHODS:Two human cohorts, consisting of healthy individuals and DCM patients, were enrolled for serum miRNA sequencing (10 vs. 10) and quantitative polymerase chain reaction validation (46 vs. 54), respectively. Rigorous screening strategy was enacted to define DACMs and their potentials for diagnosis. DCM mouse model, different sources of cardiomyocytes, adeno-associated virus 9 (AAV9), gene knockout, RNAscope miRNA in situ hybridization, mRFP-GFP-LC3B reporter, echocardiography and transmission electron microscopy were adopted for mechanistic explorations.RESULTS:Serum miRNA sequencing revealed a unique expression pattern for DCM circulating miRNAs. DACMs miR-26a-5p, miR-30c-5p, miR-126-5p and miR-126-3p were found to be depleted in DCM circulation as well as heart tissues. Their expressions in circulation and heart tissues were proven to be correlated significantly, and a combination of these miRNAs was suggested potential values for DCM diagnosis. FOXO3, a predicted common target, was experimentally demonstrated to be co-repressed within cardiomyocytes by these DACMs except miR-26a-5p. Delivery of a combination of miR-30c-5p, miR-126-5p and miR-126-3p into the murine myocardium via AAV9 carrying an expression cassette driven by cTnT promoter, or cardiac-specific knockout of FOXO3 (Myh6-CreERT2 , FOXO3 flox+/+ ) dramatically attenuated cardiac apoptosis and autophagy involved in DCM progression. Moreover, competitively disrupting the interplay between DACMs and FOXO3 mRNA by specifically introducing their interacting regions into murine myocardium crippled the cardioprotection of DACMs against DCM.CONCLUSIONS:Circulating cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and excessive autophagy in DCM development, which may provide serological cues for DCM non-invasive diagnosis and shed light on DCM pathogenesis and therapeutic targets.
Clinical and translational medicine 2023
Doxorubicin (DOX) is a chemotherapeutic agent that can cause cardiotoxicity leading to progressive, chronic, life-threatening cardiomyopathy, called DOX-induced cardiomyopathy (DIC). DIC is a fatal cardiomyopathy with a worse prognosis compared to other cardiomyopathies and limits the use of DOX in malignancies due to its cardiotoxicity. DIC has been proven to be associated with reactive oxygen species (ROS)-induced side effect damage in cardiac myocytes. Currently, scavenging of reactive oxygen species is a practical strategy to reduce chemotherapy-associated DIC. Although quercetin has already been reported to have superior antioxidant activity, its clinical application is severely limited due to its rapid degradation and poor tissue absorption. Herein, we reported the preparation of a novel enzyme mimic via coordinated albumin, Zinc Ion (Zn2+) and quercetin. The enzyme mimics were capable of simultaneously increasing the biocompatibility and efficiently overcame the drawbacks of free quercetin, and were achieved by long circulation in vivo. Most importantly, these quercetin-based enzyme mimics had no effect on the antioxidant activity of quercetin. These beneficial therapeutic properties, together with high drug-carrying capacity and redox stimuli, will significantly improve quercetin's alleviation of chemotherapeutic cardiotoxicity without causing significant side effects. Therefore, nanoparticles of albumin-based Zn (II)-Quercetin have a promising clinical application as an effective agent for mitigating the cardiotoxicity of chemotherapy.
Pharmaceuticals (Basel, Switzerland) 2022
Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured. Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal. CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis. Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction. Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis. CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability. CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP. NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not. Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.
International journal of biological sciences 2022
