Hevin Promotes Aging‐Related Cardiac Dysfunction via Facilitating Cardiac Inflammation in Male Mice

ABSTRACT As individuals age, there is a gradual increase in the levels of inflammation in the body, with macrophages, essential immune cell types, assuming a critical role in modulating inflammatory responses and eliminating senescent cells. Prolonged inflammatory reactions can result in tissue damage, the advancement of diseases, and the acceleration of aging processes. Hevin (also known as SPARCL1, secreted protein acidic and rich in cysteine‐like protein 1) is involved in regulating inflammatory responses and the polarization of macrophages. The current study seeks to elucidate the role of Hevin in the context of cardiac aging. Aging or young C57 BL/6 male mice were intravenously injected with Hevin or knocked down Hevin with adeno‐associated virus serotype 9 (AAV9) vectors. To screen the underlying mechanisms, RNA‐seq was used. Meanwhile, RAW264.7 cells were employed to investigate the role of Hevin in macrophage polarization. Aging mice displayed elevated Hevin serum levels compared to their younger counterparts, along with increased Hevin expression associated with poor cardiac function. Administration of Hevin enhanced aging‐related cardiac remodeling, whereas Hevin knockout ameliorated such remodeling and dysfunction. RNA‐seq analysis unveiled that Hevin triggered CCL5 activation in aging hearts, and blocking CCL5 reversed the adverse effects of Hevin‐induced cardiac aging in vivo. Functionally, circulating Hevin released by iWAT stimulated cardiac macrophages via TLR4, prompting their polarization and CCL5 release, exacerbating cardiac dysfunction and attracting more inflammatory cells for the secretion of pro‐inflammatory factors. During aging, Hevin expression inversely correlates with cardiac function, and its absence effectively mitigates aging‐related cardiac dysfunction by diminishing inflammatory responses. Our study uniquely identifies Hevin as a promising predictive and therapeutic target for cardiac aging.