Cardiac CD47 Drives Left Ventricular Heart Failure Through Ca ²⁺ ‐CaMKII‐Regulated Induction of HDAC3

Abstract

BackgroundLeft ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever‐larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high‐affinity secreted ligand, thrombospondin 1 (TSP1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed.Methods and ResultsIn experimental LVHF TSP1‐CD47 signaling is increased concurrent with up‐regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)‐driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1‐derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca2+/calmodulin protein kinase II (CaMKII)‐dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacologic inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals.ConclusionsThese data identify a proximate role for the TSP1‐CD47 axis in promoting LVHF by CaKMII‐mediated up‐regulation of HDAC3 and suggest novel therapeutic opportunities.

RNAi-Mediated Down-Regulation of CD47 Protects against Ischemia/Reperfusion-Induced Myocardial Damage via Activation of eNOS in a Rat Model

“…However, TSP1 does not inhibit eNOS/NO signaling in CD47-null vascular cells; in TSP1 or CD47 knockout mice, the level of NO in soft tissue increases, accompanied by raised tissue blood flow in a tissue ischemia model [33]. Sharifi-Sanjani et al found that lack of CD47 provided protection from cardiac stress and alleviated heart failure [34]. TSP1 can not only regulate the CD47, but also can activate the Nox-1 receptor to increases superoxide in vascular and epithelial cells [35,36] Previous research shows that TSP-1 has an inflammatory-associated role in myocardial infarction and MIRI [37] The basic mechanism underlying the effect of CD47 blockade in alleviating MIRI was determined by several in vivo experiments demonstrating that limitation of the CD47/TSP1 signaling pathway can alleviate IRI by increasing eNOS-derived NO signaling.…”

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

“…For instance, Ferguson et al found that class I HDAC inhibition repressed cardiac hypertrophy induced by several pathological insults in vitro via inhibition of ERK1/2 by Dual Specificity Phosphatase 5 (DUSP5) (18). Furthermore, HDAC3 was reportedly involved in different aspects of heart pathologic change, including heart failure (19), hypertrophy (20) and abnormal energy metabolism (21), but so far no information is available for its role in DCM.…”

Regulation of Cellular Redox Signaling by Matricellular Proteins in Vascular Biology, Immunology, and Cancer

“…Isolated cardiac trabecular muscle from Thbs4 -/-mice showed minimal calcium flux with sustained stretch (32). Conversely, treatment with the CD47-binding peptide 7N3 (10 lM) stimulated a rapid calcium flux in isolated rat neonatal cardiac myocytes (229). Furthermore, Thbs2 -/-mice were more sensitive to doxorubicin-mediated cardiomyopathy than WT mice (284).…”

“…NO dysregulation contributes to LV HF (221), and Nos3 -/-mice experience more LV dysfunction and fibrosis after LV pressure overload than controls (220). TSP1 but not CD47 protein was induced in the left ventricles of WT mice after 4 weeks of transverse aortic constriction (TAC) concurrent with increased histone deacetylase 3 (HDAC3) and calcium/calmodulin-dependent protein kinase II expression, and LV hypertrophy and dysfunction (229). Conversely, Cd47 -/-mice did not develop LV hypertrophy and dysfunction and had less LV HDAC3 expression both before and after TAC.…”