Adverse Effects on β‐Adrenergic Receptor Coupling: Ischemic Postconditioning Failed to Preserve Long‐Term Cardiac Function

Abstract

BackgroundIschemic preconditioning (IPC) and ischemic postconditioning (IPoC) are currently among the most efficient strategies protecting the heart against ischemia/reperfusion injury. However, the effect of IPC and IPoC on functional recovery following ischemia/reperfusion is less clear, particularly with regard to the specific receptor‐mediated signaling of the postischemic heart. The current article examines the effect of IPC or IPoC on the regulation and coupling of β‐adrenergic receptors and their effects on postischemic left ventricular function.Methods and ResultsThe β‐adrenergic signal transduction was analyzed in 3‐month‐old Wistar rats for each of the intervention strategies (Sham, ischemia/reperfusion, IPC, IPoC) immediately and 7 days after myocardial infarction. Directly after the infarction a cardioprotective potential was demonstrated for both IPC and IPoC: the infarct size was reduced, apoptosis and production of reactive oxygen species were lowered, and the myocardial tissue was preserved. Seven days after myocardial ischemia, only IPC hearts showed significant functional improvement. Along with a deterioration in fractional shortening, IPoC hearts no longer responded adequately to β‐adrenergic stimulation. The stabilization of β‐adrenergic receptor kinase‐2 via increased phosphorylation of Mdm2 (an E3‐ubiquitin ligase) was responsible for desensitization of β‐adrenergic receptors and identified as a characteristic specific to IPoC hearts.ConclusionsImmediately after myocardial infarction, rapid and transient activation of β‐adrenergic receptor kinase‐2 may be an appropriate means to protect the injured heart from excessive stress. In the long term, however, induction and stabilization of β‐adrenergic receptor kinase‐2, with the resultant loss of positive inotropic function, leads to the functional picture of heart failure.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…Interestingly, MDM2 exerts protective effects against some diseases, such as Parkinson's disease, HF, sterility, and CP . Therefore, MDM2 inhibition therapy may have a detrimental effect on these conditions.…”

“…Subsequent studies have indicated that nutlin‐3a treatment reactivates IκB, causes NFκB inactivation, and inhibits the production of proinflammatory cytokines in the post‐MI heart . Schreckenberg et al have found that immediately following MI, rapid and transient G‐protein‐coupled receptor kinase 2 (GRK2) activation may exert a protective effect against cardiac injury due to excessive stress. However, in the long term, stabilized GRK2 by increased MDM2 phosphorylation may induce cardiac dysfunction with restricted inotropic functional reserve …”

“…Schreckenberg et al have found that immediately following MI, rapid and transient G‐protein‐coupled receptor kinase 2 (GRK2) activation may exert a protective effect against cardiac injury due to excessive stress. However, in the long term, stabilized GRK2 by increased MDM2 phosphorylation may induce cardiac dysfunction with restricted inotropic functional reserve …”

Swiprosin-1/EFhD-2 Expression in Cardiac Remodeling and Post-Infarct Repair: Effect of Ischemic Conditioning

“…It was already known that in cardiomyocytes swiprosin-1 is coregulated with the mRNA expression of proteins linked to β-adrenoceptor desensitization. A desensitization of β-adrenoceptors can occur under conditions of cardiac cell cultivation and in the postischemic heart [16]. Nevertheless, coregulation of cardiac expression of swiprosin-1 and arrestin-2 in vivo has not been demonstrated before.…”

“…Among the common features between cardiac tissue repair and cellular adaptation of terminal differentiated cardiomyocytes to culture conditions are a desensitization of β-adrenoceptors that can be modified by ischemic postconditioning (IPoC) [16]. Similarly, β-adrenoceptor responsiveness is reduced during cellular adaptation of cardiomyocytes to cultivation.…”