Among the various factors leading to fatalities from cardiovascular diseases, acute myocardial infarction (AMI) stands as a major cause (Jenča et al., 2021). Innate immune cells such as monocytes and macrophages, play a crucial role in tissue injury and repair (Alisjahbana et al., 2020). However, an excessive immune response can accelerate adverse remodeling and heart failure (HF) (Adamo et al., 2020). Consequently, uncovering the primary regulators of cardiac ischemic injury may yield potential therapeutic alterations to stop and reverse the course of cardiac injury in the aftermath of myocardial infarction (MI).

Macrophages are recruited to myocardial tissue after AMI. At days 1–3 post-MI, monocyte-derived macrophages exhibit proinflammatory features to clear necrotic cells (Peet et al., 2020). Early - stage inflammatory activation creates the necessary environment for the later reparative phase (Prabhu and Frangogiannis, 2016). However, if the acute inflammatory phase of MI is not adequately suppressed or inflammation of the lower leg is delayed, it may lead to continuous tissue damage, and early wound healing disorders further aggravate cardiac systolic dysfunction. Notably, macrophages are highly plastic and can improve the prognosis of MI by adjusting their polarization (Chen et al., 2023). Studies have shown that inhibiting M1-type macrophage polarization can reduce the release inflammatory cytokines and cardiac rupture (Wan et al., 2015). Importantly, regulating the functional phenotypic transformation of macrophages may be a promising therapeutic strategy. Therefore, synchronized inflammatory responses are closely intertwined with the development process of cardiac injury post - MI and IR

Serum amyloid A1 (SAA1) is an acute-phase protein responsible for recruiting monocytes, phagocytes, and other white blood cells during the inflammatory response, and its levels can increase up to 1,000-fold in vivo under inflammatory conditions (Sun and Ye, 2016, Tamamoto et al., 2012). Moreover, SAA1 can be produced by hepatocytes, macrophages, and fibroblasts (Guz et al., 2009, Papa and Lachmann, 2018, Takehara et al., 2020). Its deficiency reduces aortic arch constriction-induced myocardial fibrosis by inhibiting the NF-κB/p38/JNK pathway (Xiao et al., 2023). However, the mechanisms by which SAA1 is involved in the regulation of post-MI inflammation have not been clarified.

Mitogen - activated protein kinases (MAPKs), which are serine and threonine protein kinases, are responsible for translating extracellular stimuli into a diverse array of cellular responses. MAPKs, including extracellular signal-regulated kinase 1/2, c-Jun N-terminal protein kinase, and p38 MAPK, modulate immune responses and other pathophysiological processes (Liu et al., 2007). A previous study demonstrated that the inhibition of the p38 MAPK signaling pathway can reduce fibrosis in hypertensive heart disease (Meijles et al., 2020). However, whether SAA1 regulates the p38 MAPK signaling pathway remains unknown.

Here, we examined the expression of SAA1 in human peripheral blood mononuclear cells (PBMCs) and ischemic myocardial tissue. Similarly, we delved into the function of SAA1 during the post-MI inflammatory response. Our findings confirmed that this protein modulates macrophage polarization through the p38 MAPK signaling pathway.