Roles of TSP1-CD47 signaling pathway in senescence of endothelial cells: cell cycle, inflammation and metabolism.

Endothelial cells (ECs) serve as a barrier with forming a monolayer lining in the surface of vascular system. Many mature cell types are post-mitotic like neurons, but ECs have the ability to grow during angiogenesis. Vascular endothelial growth factor (VEGF) stimulates growth of vascular ECs derived from arteries, veins, and lymphatics and induces angiogenesis. Senescence of ECs is regarded as a key contributor in aging-induced vascular dysfunction via evoking increase of ECs permeability, impairment of angiogenesis and vascular repair. Several genomics and proteomics studies on ECs senescence reported changes in gene and protein expression that directly correlate with vascular systemic disorder. CD47 functions as a signaling receptor for secreted matricellular protein thrombospondin-1 (TSP1) and plays an important role in several fundamental cellular functions, including proliferation, apoptosis, inflammation, and atherosclerotic response. TSP1-CD47 signaling is upregulated with age in ECs, concurrent with suppression of key self-renewal genes. Recent studies indicate that CD47 is involved in regulation of senescence, self-renewal and inflammation. In this review, we highlight the functions of CD47 in senescent ECs, including modulation of cell cycle, mediation of inflammation and metabolism by the experimental studies, which may provide CD47 as a potential therapeutic target for aging-associated vascular dysfunction.

The regulatory roles of p53 in cardiovascular health and disease.

Cardiovascular disease (CVD) remains the leading cause of mortality globally, so further investigation is required to identify its underlying mechanisms and potential targets for its prevention. The transcription factor p53 functions as a gatekeeper, regulating a myriad of genes to maintain normal cell functions. It has received a great deal of research attention as a tumor suppressor. In the past three decades, evidence has also shown a regulatory role for p53 in the heart. Basal p53 is essential for embryonic cardiac development; it is also necessary to maintain normal heart architecture and physiological function. In pathological cardiovascular circumstances, p53 expression is elevated in both patient samples and animal models. Elevated p53 plays a regulatory role via anti-angiogenesis, pro-programmed cell death, metabolism regulation, and cell cycle arrest regulation. This largely promotes the development of CVDs, particularly cardiac remodeling in the infarcted heart, hypertrophic cardiomyopathy, dilated cardiomyopathy, and diabetic cardiomyopathy. Roles for p53 have also been found in atherosclerosis and chemotherapy-induced cardiotoxicity. However, it has different roles in cardiomyocytes and non-myocytes, even in the same model. In this review, we describe the different effects of p53 in cardiovascular physiological and pathological conditions, in addition to potential CVD therapies targeting p53.

Aberrant activation of p53-TRIB3 axis contributes to diabetic myocardial insulin resistance and sulforaphane protection.

INTRODUCTION: Insulin resistance (IR) is associated with multiple pathological features. Although p53- or TRIB3-orchestrated IR is extensively studied in adipose tissue and liver, the role of p53-TRIB3 axis in myocardial IR remains unknown, and more importantly target-directed therapies of myocardial IR are missing. OBJECTIVES: Considering the beneficial effects of sulforaphane (SFN) on cardiovascular health, it is of particular interest to explore whether SFN protects against myocardial IR with a focus on the regulatory role of p53-TRIB3 axis. METHODS: Mouse models including cardiac specific p53-overexpressing transgenic (p53-cTg) mice and Trib3 knockout (Trib3-KO) mice, combined with primary cardiomyocytes treated with p53 activator (nutlin-3a) and inhibitor (pifithrin-α, PFT-α), or transfected with p53-shRNA and Trib3-shRNA, followed by multiple molecular biological methodologies, were used to investigate the role of p53-TRIB3 axis in SFN actions on myocardial IR. RESULTS: Here, we report that knockdown of p53 rescued cardiac insulin-stimulated AKT phosphorylation, while up-regulation of p53 by nutlin-3a or p53-cTg mice blunted insulin sensitivity in cardiomyocytes under diabetic conditions. Diabetic attenuation of AKT-mediated cardiac insulin signaling was markedly reversed by SFN in p53-Tgfl/fl mice, but not in p53-cTg mice. Importantly, we identified TRIB3 was elevated in p53-cTg diabetic mice, and confirmed the physical interaction between p53 and TRIB3. Trib3-KO diabetic mice displayed improved insulin sensitivity in the heart. More specifically, the AMPKα-triggered CHOP phosphorylation and degradation were essential for p53 on the transcriptional regulation of Trib3. CONCLUSION: Overall, these results indicate that inhibiting the p53-TRIB3 pathway by SFN plays an unsuspected key role in the improvement of myocardial IR, which may be a promising strategy for attenuating diabetic cardiomyopathy (DCM) in diabetic patients.

Is CD47 a potentially promising therapeutic target in cardiovascular diseases? - Role of CD47 in cardiovascular diseases.

CD47 (cluster of differentiation 47) is a ubiquitously expressed transmembrane protein that belongs to the immunoglobulin superfamily. CD47 is both a receptor for the matricellular protein thrombospondin-1 (TSP-1) and a ligand for signal-regulatory protein alpha (SIRPα). Suppression of CD47 activity enhances angiogenesis and blood flow, restores phagocytosis by macrophages, improves ischemic tissue survival, attenuates ischemia reperfusion injury, and reverses atherosclerotic plaque formation. In conclusion, these observations suggest a pathogenic role of CD47 in the development of cardiovascular diseases (CVDs) and indicate that CD47 might be a potentially promising molecular target for treating CVDs. Herein, we highlight the role of CD47 in the CVD pathogenesis and discuss the potential clinical application by targeting CD47 for treating CVDs.