Acute myocardial infarction (AMI) is a leading cause of death and major disability worldwide [[1], [2], [3]]. It is caused by the sudden occlusion of the coronary artery and leads to ischemia in the corresponding myocardial region, usually resulting in myocardial necrosis [4]. The cornerstone of therapy remains emergent myocardial reperfusion via primary percutaneous coronary intervention [5], universally regarded as the most effective strategy for AMI [[6], [7], [8]]. Prompt restoration of coronary flow curtails ischemic damage and averts cardiomyocyte death [9,10]: yet the very act of reperfusion can provoke a paradoxical, explosive injury, myocardial ischemia–reperfusion injury (MIRI) [4,11,12], that ultimately determines roughly half of the final infarct size [13]. Since reperfusion reduces mortality from myocardial infarction, much attention has been paid to exploring the pathogenesis of MIRI and strategies for its prevention and treatment [14,15].

MIRI is ignited by a network of intertwined insults, foremost among them the explosive generation of reactive oxygen species (ROS) upon reperfusion [16]. This oxidative burst destabilizes the endothelial barrier, precipitating microvascular hyperpermeability while simultaneously upregulating adhesion molecules that tether and trap leukocytes within capillaries. The ensuing cellular traffic jam and parenchymal infiltration amplify ROS production and unleash a self-propagating inflammatory cascade that magnifies myocardial damage [17,18]. Cardiac microvascular endothelial cells (CMECs) are the main barrier for the exchange of energy and nutrients between the myocardium and blood [19]. Endothelial cells (ECs), including CMECs, constitute up to one-third of all cardiac cells and play a critical role in maintaining and supporting coronary microvessels and adjacent cardiomyocytes under normal conditions and angiogenesis under pathophysiological conditions [20]. Critically, CMECs succumb to reperfusion stress earlier and more severely than cardiomyocytes, steering the earliest and most decisive events in MIRI [13]. Yet, relative to cardiomyocytes, CMECs are less studied, and the molecular mechanisms are not fully understood.

ADAMTS (a disintegrin-like and metalloproteinase with thrombospondin motif families) is a class of metalloproteinases containing thrombospondin type I repeats [21]. Family members execute diverse biological programs that govern tissue morphogenesis, pathological remodeling, inflammatory cascades, and vascular homeostasis [[22], [23], [24]]. Accumulating evidence positions the ADAMTS family as key regulators of vascular biology and cardiovascular pathophysiology [25]. ADAMTS1 [26], ADAMTS7 [27], and ADAMTS13 [28] have all been reported to be involved in myocardial injury. Besides that, ADAMTS4 has attracted our attention. ADAMTS4 is involved in cardiac development and is abnormally highly expressed in the process of myocardial injury and fibrosis [29], and the inhibition of ADAMTS4 improves cardiac dysfunction induced by mechanical stress [30]. Moreover, ADAMTS4 propagates lipopolysaccharide (LPS)-triggered endothelial injury [31], and its sustained up-regulation amplifies immune-cell infiltration and inflammatory burden in pulmonary tissue [32]. Whether this protease exerts a similar deleterious role in MIRI remains completely unexplored.

Therefore, in this study, we aim to investigate the function of ADAMTS4 on endothelial function and myocardial injury during MIRI, as well as to elucidate the potential regulatory mechanism of ADAMTS4.