Regulatory Signature of Striatin on the Adrenergic Signaling in the Failing Heart

Abstract

Cardiac failure in diabetic hearts is a serious threat to human lives with no effective therapies that can halt the progressive maladaptation of the myocardium. This owes to the paucity of information on the signaling pathways altered in this illness. Cardiac failure is characterized by unbalanced calcium homeostasis, impaired contractility, and cardiac desensitization to adrenergic stimulation. Striatin (STRN) is a protein scaffold that has multiple binding sites including caveolin (Cav), calmodulin (CaM), and protein phosphatase 2A (PP2A). The literature indicates that the adrenergic signaling pathway is altered in diabetic hearts with an overlap between insulin metabolism and adrenergic signaling. Despite the interaction of STRN with the above-mentioned proteins, the exact role of STRN in adrenergic signaling and diabetes-induced heart failure remains undefined. The purpose of this project was to assess the dynamics of STRN in a particular model of heart failure, that is diabetic cardiomyopathy (DCM), at early (8 weeks), and chronic (24 weeks) stages of diabetesin male Wistar ratstreated with streptozotocin (STZ). The data obtained indicated that these hearts were hypertrophied due to increased heart weight/body weight ratio at both 8 and 24 weeks of diabetes. STRN expression was elevated in the chronic STZ-treated hearts, but not at 8 weeks post-STZ indicating a role for STRN in chronic DCM. No variations in the expression of PP2A A subunit (PP2A-A), protein kinase A (PKA), or phosphorylated PKA (P-PKA) were noticed in the diabetic hearts. However, the expression of the catalytic subunit of PP2A (PP2A-C) was increased at early DCM in the left ventricles, but not at 24 weeks post-STZ. Interestingly, the CaM pull-down assay yielded higher interaction between CaM, STRN, and PP2A-C at 24 weeks of DCM, but not at 8 weeks of DCM. The expression of the L-type calcium channel beta subunit (LTCC) was decreased, and that of Troponin I was increased, at 8 weeks but not at 24 weeks of DCM. The cell surface area of H9c2 cells (cardiomyoblasts) overexpressing STRN and treated with the adrenergic activator forskolin was less than the control H9c2 cells indicating a role for STRN in controlling cellular hypertrophy. The data from this project provided novel insights into the dynamics of STRN in diabetic hypertrophied hearts which would possibly guide better therapies for diabetes-induced heart failure.

Date of Award	19 May 2024
Original language	American English
Supervisor	Habiba Alsafar (Supervisor)