Inhibition of integrin alpha V (CD51) reduces inflammation and transition to heart failure following pressure overload

Background Integrins are surface receptors that bind to extracellular matrix ligands and regulate cellular function through mechanical stress-initiated signal transduction. Integrin alpha V (or CD51) is implicated in myocardial fibrosis and anti-CD51 therapy improves cardiac function and cardiac fibrotic remodeling following myocardial infarction. However, their contribution in non-ischemic pressure-overload induced heart failure has not been established. Methods We implanted male C57BL/6J wild-type mice with osmotic minipumps containing a combination of AngII (1.44mg/kg/day) and the α1 adrenergic agonist Phenylephrine (PE)(50mg/kg/day) to induce hypertrophic heart failure. Treatment with AngII alone was used as a model of compensated cardiac hypertrophy. Mice treated with PE or saline were used as controls. Animals were treated with daily intraperitoneal injections of the anti-CD51 molecule cilengitide or vehicle. Cardiac echography, flow cytometry, histological, and protein analyses were used to study the development of fibrosis and cardiac adverse remodeling. Results Mice treated with the combination of AngII and PE showed maladaptive cardiac hypertrophy associated with a fibrotic remodeling and a rapid transition to heart failure. CD51 protein expression and CD51+ cell number were increased in the myocardium of these animals. In contrast, mice treated with AngII alone exhibited compensated cardiac hypertrophy with low levels of fibrosis, no signs of congestive heart failure, and no changes in cardiac CD51 expression as well as CD51+ cell number. Anti-CD51 therapy in mice receiving AngII + PE significantly reduced the transition to heart failure and the development of cardiac fibrosis. Anti-CD51 therapy notably reduced the recruitment of monocyte-derived pro-inflammatory CCR2+ cardiac macrophages, which also showed a high expression of CD51 at their surface. Macrophages sense matrix stiffness and activate a pro-inflammatory response to stiffer substrates, a response that was blunted by anti-CD51 therapy. Conclusion Anti-CD51 therapy reduces the transition to heart failure in response to pressure overload and modulates the pro-inflammatory and deleterious action of CD51+ myeloid cells. We identified CD51 inhibition as a novel therapeutic strategy for reducing the progression of non-ischemic and pressure-dependent heart failure. Clinical perspectives What is new? What are the clinical implications? ### Competing Interest Statement JSH reports research grants to the institution from Bioserenity, Pliant Thx, Sanofi, Servier; speaker, advisory board, or consultancy fees from Alnylam, Amgen, Astra Zeneca, Bayer, Bioserenity, Boerhinger Ingelheim, MSD, Novartis, Novo Nordisk, Vifor Pharma, all unrelated to the present work. Other authors declare no competing financial interests.