Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

Cittadini, Antonio; Monti, Maria Gaia; Iaccarino, Guido; Rella, Francesca Di; Tsichlis, P N; Gianni, Angela Di; Strömer, Hinrik; Sorriento, Daniela; Peschle, Cesare; Trimarco, Bruno; Saccà, Luigi; Condorelli, Gianluigi

doi:10.1038/sj.gt.3302589

Cited by 60 publications

(50 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Mechanistically, the increased ability of the SR to sequester Ca 2ϩ was due to an increase in protein expression of SERCA and not due to changes in the expression or phosphorylation status of the SERCA inhibitory protein PLB (21). These data are in agreement with studies using adenoviral or TG overexpression of active Akt in rodents, which increased SERCA expression and enhanced contractile function (3,19). Notably, cardiac overexpression of SERCA alone results in enhanced Ca 2ϩ transients and hypercontractility (13).…”

Section: Discussionsupporting

confidence: 79%

“…This leads to enhanced growth signaling and thereby cardiomyocyte hypertrophy. Hyperactivation of Akt has previously been shown to increase intracellular Ca 2ϩ availability and enhance cardiac contractility (3,4,19). In classic HCM, changes in calcium handling and Ca 2ϩ sensitivity and/or alterations in the biophysical properties of the contractile apparatus are thought to be critical to the pathomechanism (10).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Clay

Domeier

Hanft

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Clay SA, Domeier TL, Hanft LM, McDonald KS, Krenz M. Elevated Ca 2ϩ transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines. Am J Physiol Heart Circ Physiol 308: H1086 -H1095, 2015. First published February 27, 2015 doi:10.1152/ajpheart.00501.2014.-Noonan syndrome with multiple lentigines (NSML) is primarily caused by mutations in the nonreceptor protein tyrosine phosphatase SHP2 and associated with congenital heart disease in the form of pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM). Our goal was to elucidate the cellular mechanisms underlying the development of HCM caused by the Q510E mutation in SHP2. NSML patients carrying this mutation suffer from a particularly severe form of HCM. Drawing parallels to other, more common forms of HCM, we hypothesized that altered Ca 2ϩ homeostasis and/or sarcomeric mechanical properties play key roles in the pathomechanism. We used transgenic mice with cardiomyocyte-specific expression of Q510E-SHP2 starting before birth. Mice develop neonatal onset HCM with increased ejection fraction and fractional shortening at 4 -6 wk of age. To assess Ca 2ϩ handling, isolated cardiomyocytes were loaded with fluo-4. Q510E-SHP2 expression increased Ca 2ϩ transient amplitudes during excitation-contraction coupling and increased sarcoplasmic reticulum Ca 2ϩ content concurrent with increased expression of sarco(endo)plasmic reticulum Ca 2ϩ -ATPase. In skinned cardiomyocyte preparations from Q510E-SHP2 mice, force-velocity relationships and power-load curves were shifted upward. The peak power-generating capacity was increased approximately twofold. Transmission electron microscopy revealed that the relative intracellular area occupied by sarcomeres was increased in Q510E-SHP2 cardiomyocytes. Triton X-100-based myofiber purification showed that Q510E-SHP2 increased the amount of sarcomeric proteins assembled into myofibers. In summary, Q510E-SHP2 expression leads to enhanced contractile performance early in disease progression by augmenting intracellular Ca 2ϩ cycling and increasing the number of power-generating sarcomeres. This gives important new insights into the cellular pathomechanisms of Q510E-SHP2-associated HCM. contractility; sarcomeric function; sarco(endo)plasmic reticulum Ca 2ϩ -ATPase; cardiac hypertrophy; protein tyrosine phosphatase HYPERTROPHIC CARDIOMYOPATHY (HCM) affects ϳ1:500 adults (31) and represents one of the most common causes of sudden cardiac death in young individuals (49). Often the disease is detected in early adolescence, when patients develop arrhythmias, exercise intolerance, chest pain, or even sudden cardiac death. Classically, HCM is characterized by concentric myocardial hypertrophy with cardiomyocyte disarray. Outflow tract obstruction resulting from segmental septal hypertrophy or systolic anterior motion of the mitral valve often augments the disease. The majority of the genetic mutations reported in patients with familial HCM affect components of ...

show abstract

Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Clay

Domeier

Hanft

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…Overexpression of Akt in adult rat hearts using an adenoviral gene transfer method enhanced myocyte contractility (28). Conceivably, strategies that activate the PI 3-kinase/Akt pathway can be developed to enhance the contractility of a failing heart.…”

Section: Discussionmentioning

confidence: 99%

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Jiang

et al. 2007

Diabetes

View full text Add to dashboard Cite

OBJECTIVE-Contraction of cardiac myocytes is initiated byCa 2ϩ entry through the voltage-dependent L-type Ca 2ϩ channel (LTCC). Previous studies have shown that phosphatidylinositol (PI) 3-kinase signaling modulates LTCC function. Because PI 3-kinases are key mediators of insulin action, we investigated whether LTCC function is affected in diabetic animals due to reduced PI 3-kinase signaling. RESEARCH DESIGN AND METHODS-We used whole-cell patch clamping and biochemical assays to compare cardiac LTCC function and PI 3-kinase signaling in insulin-deficient diabetic mice heterozygous for the Ins2 Akita mutation versus nondiabetic littermates.RESULTS-Diabetic mice had a cardiac contractility defect, reduced PI 3-kinase signaling in the heart, and decreased L-type Ca 2ϩ current (I Ca,L ) density in myocytes compared with control nondiabetic littermates. The lower I Ca,L density in myocytes from diabetic mice is due at least in part to reduced cell surface expression of the LTCC. I Ca,L density in myocytes from diabetic mice was increased to control levels by insulin treatment or intracellular infusion of PI 3,4,5-trisphosphate [PI(3,4,5)P 3 ]. This stimulatory effect was blocked by taxol, suggesting that PI(3,4,5)P 3 stimulates microtubule-dependent trafficking of the LTCC to the cell surface. The voltage dependence of steady-state activation and inactivation of I Ca,L was also shifted to more positive potentials in myocytes from diabetic versus nondiabetic animals. PI(3,4,5)P 3 infusion eliminated only the difference in voltage dependence of steady-state inactivation of I Ca,L .CONCLUSIONS-Decreased PI 3-kinase signaling in myocytes from type 1 diabetic mice leads to reduced Ca 2ϩ entry through the LTCC, which might contribute to the negative effect of diabetes on cardiac contractility. Diabetes 56:2780-2789, 2007 C ardiac complications are an important cause of morbidity and mortality in type 1 diabetic patients. This is partly due to the presence of hypertension and coronary artery disease, which are commonly associated with diabetes. Diabetes also increases the risk of developing cardiac dysfunction independently of these risk factors, supporting the existence of a distinct diabetic cardiomyopathy (1). A number of studies have shown that Ca 2ϩ entry through the voltagedependent L-type Ca 2ϩ channel (LTCC) is reduced in cardiac myocytes from streptozotocin-induced diabetic rats and from obese db/db mice, a well-known model of type 2 diabetes (2-5). This inward Ca 2ϩ current (I Ca,L ) is the critical initiator of the contractile cycle in cardiac myocytes, and inhibition of LTCC function would reduce Ca 2ϩ entry and contractile force. However, the molecular mechanism that underlies the LTCC defect in diabetic myocytes is unclear.Class I phosphatidylinositol (PI) 3-kinases preferentially phosphorylate PI 4,5-bisphosphate [PI(4,5)P 2 ] to form phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ] in vivo and exhibit substantial activation in response to stimulation with insulin or other hormones. Studies in neuron...

show abstract

“…], with marginal increased myocardial oxygen consumption (53). The reduced oxygen consumption required for Ca 2+ transport in turn limits the threat of arrhythmias and results in inhibition of Ca…”

Section: +mentioning

confidence: 99%

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Bhuiyan

Fukunaga

2009

J Pharmacol Sci

View full text Add to dashboard Cite

Abstract. Treatment with inorganic and organic compounds of vanadium has been shown to exert a wide range of cardioprotective effects in myocardial ischemia/reperfusion-induced injury, myocardial hypertrophy, hypertension, and vascular diseases. Furthermore, administration of vanadium compounds improves cardiac performance and smooth muscle cell contractility and modulates blood pressure in various models of hypertension. Like other vanadium compounds, we documented bis(1-oxy-2-pyridinethiolato) oxovanadium (IV) [VO(OPT)] as a potent cardioprotective agent to elicit cardiac functional recovery in myocardial infarction and pressure overload-induced hypertrophy. Vanadium compounds activate Akt signaling through inhibition of protein tyrosine phosphatases, thereby eliciting cardioprotection in myocardial ischemia / reperfusion-induced injury and myocardial hypertrophy. Vanadium compounds also promote cardiac functional recovery by stimulation of glucose transport in diabetic heart. We here discuss the current understanding of mechanisms underlying vanadium compound-induced cardioprotection and propose a novel therapeutic strategy targeting for Akt signaling to rescue cardiomyocytes from heart failure.

show abstract

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

Cited by 60 publications

References 41 publications

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Contact Info

Product

Resources

About

Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling

Cited by 60 publications

References 41 publications

Elevated Ca2+transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Elevated Ca2+transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Decreased l-Type Ca2+ Current in Cardiac Myocytes of Type 1 Diabetic Akita Mice Due to Reduced Phosphatidylinositol 3-Kinase Signaling

Cardioprotection by Vanadium Compounds Targeting Akt-Mediated Signaling

Contact Info

Product

Resources

About

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines

Elevated Ca²⁺transients and increased myofibrillar power generation cause cardiac hypercontractility in a model of Noonan syndrome with multiple lentigines