The CD4⁺AT2R⁺ T cell subpopulation improves post‐infarction remodelling and restores cardiac function

Abstract

Myocardial infarction (MI) is a major condition causing heart failure (HF). After MI, the renin angiotensin system (RAS) and its signalling octapeptide angiotensin II (Ang II) interferes with cardiac injury/repair via the AT1 and AT2 receptors (AT1R, AT2R). Our study aimed at deciphering the mechanisms underlying the link between RAS and cellular components of the immune response relying on a rodent model of HF as well as HF patients. Flow cytometric analyses showed an increase in the expression of CD4+ AT2R+ cells in the rat heart and spleen post-infarction, but a reduction in the peripheral blood. The latter was also observed in HF patients. The frequency of rat CD4+ AT2R+ T cells in circulating blood, post-infarcted heart and spleen represented 3.8 ± 0.4%, 23.2 ± 2.7% and 22.6 ± 2.6% of the CD4+ cells. CD4+ AT2R+ T cells within blood CD4+ T cells were reduced from 2.6 ± 0.2% in healthy controls to 1.7 ± 0.4% in patients. Moreover, we characterized CD4+ AT2R+ T cells which expressed regulatory FoxP3, secreted interleukin-10 and other inflammatory-related cytokines. Furthermore, intramyocardial injection of MI-induced splenic CD4+ AT2R+ T cells into recipient rats with MI led to reduced infarct size and improved cardiac performance. We defined CD4+ AT2R+ cells as a T cell subset improving heart function post-MI corresponding with reduced infarction size in a rat MI-model. Our results indicate CD4+ AT2R+ cells as a promising population for regenerative therapy, via myocardial transplantation, pharmacological AT2R activation or a combination thereof.

Myocardial aging as a T-cell–mediated phenomenon

“…During the last couple of years, our group demonstrated that ischemic, sterile myocardial injuries can elicit lymphocyte activation directed against cardiac antigens (13)(14)(15)(16). Our previous data, showing for the first time that CD4 + T cells reactive to cardiac components can foster the healing process that takes place after myocardial infarction, were corroborated by several other reports (13,15,(17)(18)(19)(20). However, these autoreactive T cells can also be potentially deleterious (21).…”

Sex Differences in Hypertension

“…This data suggests a beneficial role for T cell AT 1 -stimulation in males that is independent of BP. While little is known regarding the role of AT 2 receptors on T cells in Ang II hypertension, intramyocardial injection of T cells expressing the AT 2 receptor reduced infarct size and improved cardiac performance post myocardial infarction in male rats suggesting a beneficial role for T cell AT 2 receptors in cardiovascular disease as well 29 . RAS receptor expression on T cells in females have yet to be studied, although sex differences in AT 1 /AT 2 receptor expression on immune cells may also serve as a potential mediator for the observed sex difference in T cells.…”

Cardiac Mesenchymal Stem Cells Proliferate Early in the Ischemic Heart

“…Cardiac mononuclear cells (MNCs) were isolated from infarcted (MI group) and healthy (sham group) hearts 24 h after surgery as previously described [13]. Briefly, rat hearts were minced into small pieces (1–2 mm 3 ) and kept in HBSS (with Ca 2+ and Mg 2+ ; Thermo Fisher Scientific) followed by digestion within an enzymatic cocktail containing collagenase I, collagenase XI, hyaluronidase, and DNase I (all Sigma-Aldrich).…”