Abstract 404: FK506-binding Protein 38 Protects the Heart From Pressure Overload-induced Cardiac Dysfunction via Endoplasmic Reticulum-associated Apoptosis

Abstract

Backgrounds: FK506-binding protein 38 (FKBP38) is a membrane chaperone with its peptidyl-prolyl cis-trans isomerase activity, localized to mitochondria and endoplasmic reticulum. It has been reported that chaperone systems in the heart play a protective role against the toxicity of misfolded proteins during the development of heart failure, but the pathophysiological effect of FKBP38 in the heart has not been investigated. Methods and Results: To study the role of FKBP38 in the heart, we have generated cardiac-specific FKBP38 knockout (KO) mice. KO mice had no effect on cardiac function compared to wild type (WT) littermates under unstressed conditions at 8 to 10 weeks old. The mice were subjected to transverse aortic constriction (TAC) or Sham surgeries. Echocardiography demonstrated that KO mice showed significantly decreased fractional shortening and increased end-diastolic left ventricular dimension compared to WT mice 1 week after TAC (20.7 + 2.6 vs 39.3 + 2.4%, 3.92 + 0.4 vs 3.32 + 0.4 mm, P<0.01, respectively). TAC-operated KO mice exhibited similar heart weight/tibial length (11.1 + 0.2 vs 11.8 + 0.3 mg/mm, P=NS) but significantly higher lung weight/tibial length (13.7 + 1.0 vs 9.4 + 0.3 mg/mm, P<0.01) compared to TAC-operated WT, indicating that KO mice had more progressive left ventricular dysfunction with pulmonary congestion in response to pressure overload. TUNEL staining revealed that the numbers of TUNEL positive nuclei of cardiomyocytes were dramatically increased in KO mice compared to WT mice after TAC (140 + 13 vs 25 + 9 per 10 5 nuclei, P<0.01). To understand further mechanisms of apoptosis, we estimated the activation of caspase 12, which is responsible for ER stress-induced apoptosis. The expression levels of cleaved caspase 12 were significantly elevated in KO mice compared to WT mice after TAC. Moreover, the expression levels of ER stress markers such as 94 kDa glucose-regulated protein, 78 kDa glucose-regulated protein and protein disulfide-isomerase were significantly upregulated in KO mice compared to WT mice after TAC. Conclusion: Our findings demonstrate for the first time that FKBP38 plays protective effects in the heart against pressure overload-induced cardiac dysfunction via endoplasmic reticulum-associated apoptosis.