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.

Providers seeking to elicit addiction-related clinical history and facilitate SUR and SUT might look to the current findings for guidance. Provider training in motivational interviewing may be warranted, which allows for an exploration of health-related consequences of SU and supports patients' self-efficacy.

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