Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology integrative and comparative physiology, 2008-11, Vol.295 (5), p.R1439-R1445
• Main Authors: Suarez, Jorge, Scott, Brian, Dillmann, Wolfgang H
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Animals; Anti-Bacterial Agents - pharmacology; Biochemistry; Blotting, Western; Calcium; Calcium - metabolism; Calcium Signaling - physiology; Cardiology; Cardiovascular disease; Diabetes; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - metabolism; Diabetic Angiopathies - physiopathology; Doxycycline - pharmacology; Echocardiography; Endocrine Physiology and Metabolism; Heart Ventricles; In Vitro Techniques; Mice; Mice, Transgenic; Myocardial Contraction - genetics; Myocardial Contraction - physiology; Myocytes, Cardiac - physiology; Proteins; Rodents; Sarcoplasmic Reticulum Calcium-Transporting ATPases - biosynthesis; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics
• ISSN: 0363-6119; 1522-1490
• DOI: 10.1152/ajpregu.00736.2007

Department of Medicine, University of California, San Diego, La Jolla, California Submitted 9 October 2007 ; accepted in final form 12 September 2008 Diabetic cardiomyopathy is characterized by reduced cardiac contractility independent of vascular disease. A contributor to contractile dysfunction in the diabetic heart is impaired sarcoplasmic reticulum function with reduced sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA2a) pump activity, leading to disturbed intracellular calcium handling. It is currently unclear whether increasing SERCA2a activity in hearts with existing diabetic cardiomyopathy could still improve calcium flux and contractile performance. To test this hypothesis, we generated a cardiac-specific tetracycline-inducible double transgenic mouse, which allows for doxycycline (DOX)-based inducible SERCA2a expression in which DOX exposure turns on SERCA2a expression. Isolated cardiomyocytes and Langendorff perfused hearts from streptozotocin-induced diabetic mice were studied. Our results show that total SERCA2a protein levels were decreased in the diabetic mice by 60% compared with control. SERCA2a increased above control values in the diabetic mice after DOX. Dysfunctional contractility in the diabetic cardiomyocyte was restored to normal by induction of SERCA2a expression. Calcium transients from diabetic cardiomyocytes showed a delayed rate of diastolic calcium decay of 66%, which was reverted toward normal after SERCA2a expression induced by DOX. Global cardiac function assessed in the diabetic perfused heart showed diminished left ventricular pressure, rate of contraction, and relaxation. These parameters were returned to control values by SERCA2a expression. In conclusion, we have used mice allowing for inducible expression of SERCA2a and could demonstrate that increased expression of SERCA2a leads to improved cardiac function in mice with an already established diabetic cardiomyopathy in absence of detrimental effects. transgenic mice; doxycycline; cardiac myocytes Address for reprint requests and other correspondence: W. H. Dillmann, Dept. of Medicine, 5063 Basic Sciences Bldg., Univ. of California, San Diego, La Jolla, CA 92093-0618 (e-mail: wdillmann{at}ucsd.edu )