Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer

Satoh, Susumu; Lebeche, Djamel; Sakata, Yuri; Sakata, Naoya; Chemaly, Elie R.; Li, Liang; Padmanabhan, Prabhu; Konishi, Noboru; Takaki, Miyako; Monte, Federica del; Hajjar, Roger J.

doi:10.1016/j.ymthe.2006.01.002

Cited by 51 publications

(61 citation statements)

References 33 publications

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“…We have previously shown that SERCA overexpression protects the heart against the decrease in contractile function which accompanies diabetes (47). Recent work by Sakata et al (40), using adenovirally mediated SERCA expression in rat hearts, has shown an improvement in energy utilization and oxygen consumption in a rat model of Type 2 diabetes. It should also be noted that adenovirally mediated SERCA overexpression did improve the ATP-to-PCr ratio in hypertrophied rat hearts (10), and we have shown an improved function in a pressure overload model of hypertrophy involving aortic-banded transgenic mice with doxycycline-inducible SERCA expression (43).…”

Section: Discussionmentioning

confidence: 93%

Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

Belke¹,

Swanson²,

Suárez³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Dillmann WH. Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose. Am J Physiol Heart Circ Physiol 292: H1755-H1763, 2007. First published December 1, 2006; doi:10.1152/ajpheart.00884.2006.-While several transgenic mouse models exhibit improved contractile characteristics in the heart, less is known about how these changes influence energy metabolism, specifically the balance between carbohydrate and fatty acid oxidation. In the present study we examine glucose and fatty acid oxidation in transgenic mice, generated to overexpress sarco(endo) plasmic reticulum calcium-ATPase (SERCA), which have an enhanced contractile phenotype. Energy substrate metabolism was measured in isolated working hearts using radiolabeled glucose and palmitate. We also examined oxygen consumption to see whether SERCA overexpression is associated with increased oxygen utilization. Since SERCA is important in calcium handling within the cardiac myocyte, we examined cytosolic calcium transients in isolated myocytes using indo-1, and mitochondrial calcium levels using pericam, an adenovirally expressed, mitochondrially targeted ratiometric calcium indicator. Oxygen consumption did not differ between wildtype and SERCA groups; however, we were able to show an increased utilization of glucose for oxidative metabolism and a corresponding decreased utilization of fatty acids in the SERCA group. Cytosolic calcium transients were increased in myocytes isolated from SERCA mice, and they show a faster rate of decay of the calcium transient. With these observations we noted increased levels of mitochondrial calcium in the SERCA group, which was associated with an increase in the active form of the pyruvate dehydrogenase complex. Since an increase in mitochondrial calcium levels leads to activation of the pyruvate dehydrogenase complex (the rate-limiting step for carbohydrate oxidation), the increased glucose utilization observed in isolated perfused hearts in the SERCA group may reflect a higher level of mitochondrial calcium. mitochondrial calcium; pyruvate dehydrogenase; cardiac energetics; sarco(endo)plasmic reticulum calcium-adenosine 5Ј-triphosphatase IN THE HEART, OXIDATIVE METABOLISM involving ATP production and workload are tightly linked. An increase in cardiac output is associated with an increase in oxygen consumption and an increase in energy substrate metabolism (carbohydrates and fatty acids) (36). An increase in cardiac performance occurs in vivo as a result of increased stimulation by the sympathetic nervous system and can be mimicked in ex vivo isolated heart preparations (Langendorff, working heart) through the use of positive inotropic agents (dobutamine and isoproterenol), an increase in heart rate, an increase in perfusate calcium concentrations, and/or an increase in preload and afterload perfusion pressures (19,23,35,42). The increased cardiac performance is associated with an increased calcium load within the myocyte, affecting the increase in force generation (23). In an att...

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Section: Discussionmentioning

confidence: 93%

Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

Belke¹,

Swanson²,

Suárez³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…It is interesting to note that we have demonstrated, in previous studies, that SERCA2a overexpression increased mitochondrial calcium levels, which was associated with an increase in the active form of the pyruvate dehydrogenase complex (3). Furthermore, it has been demonstrated that adenoviral gene transfer of SERCA2a improved energetic parameters in a type II diabetic model transforming inefficient energy utilization into a more efficient state (14).…”

Section: Discussionmentioning

confidence: 99%

“…It remains unclear, however, whether an established diabetic cardiomyopathy with diminished contractile function and abnormal Ca 2ϩ handling can be reverted toward normal by inducible expression of SERCA2a in cardiac myocytes. It has been reported that adenoviral gene transfer of SERCA2a to the whole heart in vivo improved left ventricular mechanical and energetic functions in a type II diabetes model of cardiomyopathy in rats (14); however, no data is available regarding Ca 2ϩ handling or contractility at the cardiac myocyte level. The lack of information at the cellular level using an adenoviral gene transfer approach may be due to technical difficulties to assess calcium handling and cell shortening in transfected cardiac myocytes, since adenoviral transfer is inhomogeneous.…”

mentioning

confidence: 99%

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

Suárez¹,

Scott²,

Dillmann³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Suarez J, Scott B, Dillmann WH. Conditional increase in SERCA2a protein is able to reverse contractile dysfunction and abnormal calcium flux in established diabetic cardiomyopathy. Am J Physiol Regul Integr Comp Physiol 295: R1439 -R1445, 2008. First published September 17, 2008 doi:10.1152/ajpregu.00736.2007.-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 2ϩ -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 CONGESTIVE HEART FAILURE IS an important medical problem resulting in significant morbidity and mortality. Heart failure occurs at an increased incidence in patients with diabetes mellitus. In addition to an increased propensity for coronary vascular disease, resulting in ischemic heart disease, diabetic cardiomyopathy occurs in combination with or independent of coronary vascular disease (12). In the diabetic heart, abnormal Ca 2ϩ handling during the contractile cycle results in a decreased upstroke phase of the Ca 2ϩ transient due to diminished release of Ca 2ϩ from the sarcoplasmic reticulum (SR) by ryanodine receptor (RyR2) (2, 17). In addition, the diastolic decline of the Ca 2ϩ transient is diminished due to reduced activity of the sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA2a) pump (5).Most functional studies indicate decreased SERCA2a activity and protein...

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“…It has been shown that increasing the activity of SERCA2a via gene transfer increases contractility in isolated failing human cardiac myocytes 2 and leads to an improvement in cardiac function and metabolism in animal models of HF. [3][4][5][6][7][8] A phase 1 trial of 12 patients with advanced HF treated with 1 of 4 dose cohorts of recombinant adeno-associated viral vector serotype 1 (AAV1) containing human SERCA2a gene (AAV1/SERCA2a) 9,10 established preliminary safety, which led to a phase 2 randomized, double-blind, placebo-controlled trial. In this study, the effectiveness of 3 different dose cohorts of AAV1/SERCA2a versus placebo was evaluated in 39 patients with advanced HF.…”

Section: In This Issue See Pmentioning

confidence: 99%

Long-Term Effects of AAV1/SERCA2a Gene Transfer in Patients With Severe Heart Failure

Zsebo

Yaroshinsky

Rudy

et al. 2014

Circulation Research

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274

205

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Objective: To report long-term (3-year) clinical effects and transgene expression in the patients in CUPID 1. Methods and Results: A total of 39 patients with advanced heart failure who were on stable, optimal heart failure therapy were randomized to receive intracoronary infusion of AAV1/SERCA2a in 1 of 3 doses (low-dose, 6×10 11 DNase-resistant particles; mid-dose, 3×1012 DNase-resistant particles; and high-dose, 1×10 13 DNase-resistant particles) versus placebo. The following recurrent cardiovascular and terminal events were tracked for 3 years in all groups: myocardial infarction, worsening heart failure, heart failure-related hospitalization, ventricular assist device placement, cardiac transplantation, and death. The number of cardiovascular events, including death, was highest in the placebo group, high but delayed in the low-and mid-dose groups, and lowest in the high-dose group. Evidence of long-term transgene presence was also observed in high-dose patients. The risk of prespecified recurrent cardiovascular events was reduced by 82% in the high-dose versus placebo group (P=0.048). No safety concerns were noted during the 3-year follow-up. Conclusions:

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Mechanical and metabolic rescue in a type II diabetes model of cardiomyopathy by targeted gene transfer

Cited by 51 publications

References 33 publications

Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

Increased expression of SERCA in the hearts of transgenic mice results in increased oxidation of glucose

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

Long-Term Effects of AAV1/SERCA2a Gene Transfer in Patients With Severe Heart Failure

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