Abstract Body: Background: Molecular chaperones are increasingly recognized as key modulators of cardiac stress responses, including protection against pathological remodeling and heart failure following ischemia/reperfusion (I/R) injury. The sigma-1 receptor (Sigmar1), a molecular chaperone enriched at mitochondria-associated membranes, is highly expressed in the heart. However, its role in myocardial stress adaptation and I/R-induced cardiac injury remains poorly defined.
Objective: This study aimed to determine the functional significance of Sigmar1 in regulating cardiac injury, remodeling, and contractile dysfunction following I/R stress.
Methods and Results: Sigmar1 was constitutively expressed in the myocardium and was significantly upregulated following I/R injury. To define its physiological role in cardiac stress responses, we generated cardiac-specific Sigmar1 transgenic (Tg) mice and utilized Sigmar1 knockout (KO) mice. Under basal conditions, Sigmar1 Tg mice exhibited normal cardiac morphology, ultrastructure, and hemodynamic function, indicating that Sigmar1 overexpression does not perturb physiological cardiac homeostasis. Following I/R injury, Sigmar1 Tg hearts demonstrated markedly reduced infarct size at 24 hours of reperfusion and were protected from long-term adverse ventricular remodeling, with preserved cardiac contractile function up to 12 weeks post-injury. In contrast, Sigmar1 deficiency resulted in baseline alterations in cardiac ultrastructure and hemodynamic parameters. Moreover, Sigmar1 KO mice exhibited increased susceptibility to I/R injury, characterized by larger infarct size, exacerbated pathological remodeling, and severe deterioration of cardiac function.
Conclusions: These findings establish Sigmar1 as a critical regulator of myocardial stress adaptation and cardioprotection. By limiting ischemic injury and suppressing maladaptive post-ischemic remodeling, Sigmar1 functions as an endogenous protective chaperone that preserves cardiac structure and function following I/R stress.
Keywords: Sigmar1, ischemia/reperfusion injury, heart fibrosis, mitochondria