Overexpression of adenylyl cyclase type 5 (AC5) confers a proarrhythmic substrate to the heart.
American Journal of Physiology - Heart and Circ... 308(3):H240 (2015)
Inhibition of β-adrenergic receptor (β-AR) signaling is one of the most common therapeutic approaches for patients with arrhythmias. Adenylyl cyclase (AC) is the key enzyme responsible for transducing β-AR stimulation to increases in cAMP. The two major AC isoforms in the heart are types 5 and 6...
Cardiac specific expression of threonine 5 to alanine mutant sarcolipin results in structural remodeling and diastolic dysfunction.
PLoS ONE 10(2):e0115822 (2015)
The functional importance of threonine 5 (T5) in modulating the activity of sarcolipin (SLN), a key regulator of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) pump was studied using a transgenic mouse model with cardiac specific expression of threonine 5 to alanine mutant SLN (SLNT5A). In...
Increased sarcolipin expression and adrenergic drive in humans with preserved left ventricular ejection fraction and chronic isolated mitral regurgitation.
Circulation: Heart Failure 7(1):194 (2014)
There is currently no therapy proven to attenuate left ventricular (LV) dilatation and dysfunction in volume overload induced by isolated mitral regurgitation (MR). To better understand molecular signatures underlying isolated MR, we performed LV gene expression analyses and overlaid regulated g...
Altered active zones, vesicle pools, nerve terminal conductivity, and morphology during experimental MuSK myasthenia gravis.
PLoS ONE 9(12):e110571 (2014)
Recent studies demonstrate reduced motor-nerve function during autoimmune muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG). To further understand the basis of motor-nerve dysfunction during MuSK-MG, we immunized female C57/B6 mice with purified rat MuSK ectodomain. Nerve-muscle prep...
Increased sarcolipin expression and decreased sarco(endo)plasmic reticulum Ca2+ uptake in skeletal muscles of mouse models of Duchenne muscular dystrophy.
Journal of Muscle Research and Cell Motility 34(5-6):349 (2013)
Abnormal intracellular Ca(2+) handling is an important factor in the progressive functional decline of dystrophic muscle. In the present study, we investigated the function of sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase (SERCA) in various dystrophic muscles of mouse models of Duchenne muscul...
Xanthine oxidase inhibition preserves left ventricular systolic but not diastolic function in cardiac volume overload.
American Journal of Physiology - Heart and Circ... 305(10):H1440 (2013)
Xanthine oxidase (XO) is increased in human and rat left ventricular (LV) myocytes with volume overload (VO) of mitral regurgitation and aortocaval fistula (ACF). In the setting of increased ATP demand, XO-mediated ROS can decrease mitochondrial respiration and contractile function. Thus, we tes...
SMB myosin heavy chain knockout enhances tonic contraction and reduces the rate of force generation in ileum and stomach antrum.
American Journal of Physiology - Cell Physiology 304(2):C194 (2013)
The role of SMA and SMB smooth muscle myosin heavy chain (MHC) isoforms in tonic and phasic contractions was studied in phasic (longitudinal ileum and stomach circular antrum) and tonic (stomach circular fundus) smooth muscle tissues of SMB knockout mice. Knocking out the SMB MHC gene eliminated...
Ablation of sarcolipin results in atrial remodeling.
American Journal of Physiology - Cell Physiology 302(12):C1762 (2012)
Sarcolipin (SLN) is a key regulator of sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA), and its expression is altered in diseased atrial myocardium. To determine the precise role of SLN in atrial Ca(2+) homeostasis, we developed a SLN knockout (sln-/-) mouse model and demonstrated that a...
Enhanced Ca2+ transport and muscle relaxation in skeletal muscle from sarcolipin-null mice.
American Journal of Physiology - Cell Physiology 301(4):C841 (2011)
Sarcolipin (SLN) inhibits sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pumps. To evaluate the physiological significance of SLN in skeletal muscle, we compared muscle contractility and SERCA activity between Sln-null and wild-type mice. SLN protein expression in wild-type mice was abundant...
Decreased sarcolipin protein expression and enhanced sarco(endo)plasmic reticulum Ca2+ uptake in human atrial fibrillation.
Biochemical and Biophysical Research Communicat... 410(1):97 (2011)
Sarcolipin (SLN), a key regulator of cardiac sarco(endo)plasmic reticulum (SR) Ca(2+) ATPase, is predominantly expressed in atria and mediates β-adrenergic responses. Studies have shown that SLN mRNA expression is decreased in human chronic atrial fibrillation (AF) and in aortic banded mouse atr...
Ablation of phospholamban and sarcolipin results in cardiac hypertrophy and decreased cardiac contractility.
Cardiovascular Research 89(2):353 (2011)
Improving the sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA) function has clinical implications in treating heart failure. The present study aimed to determine the effect of constitutive activation of the SERCA pump on cardiac contractility in normal mice and during pressure-overload-in...
Angiotensin II induces afterdepolarizations via reactive oxygen species and calmodulin kinase II signaling.
Journal of Molecular and Cellular Cardiology 50(1):128 (2011)
Renin-angiotensin system inhibitors significantly reduce the incidence of arrhythmias. However, the underlying mechanism(s) is not well understood. We aim to test the hypothesis that angiotensin II (Ang II) induces early afterdepolarizations (EADs) and triggered activities (TAs) via the nicotina...
Threonine-5 at the N-terminus can modulate sarcolipin function in cardiac myocytes.
Journal of Molecular and Cellular Cardiology 47(5):723 (2009)
Sarcolipin (SLN) has emerged as an important regulator of the atrial sarcoplasmic reticulum (SR) Ca2+ transport. The inhibitory effect of SLN on cardiac SR Ca2+ ATPase (SERCA) pump can be relieved by beta-adrenergic stimulation, which indicates that SLN is a reversible inhibitor. However, the me...
Deletion of SM-B, the high ATPase isoform of myosin, upregulates the PKC-mediated signal transduction pathway in murine urinary bladder smooth muscle.
American Journal of Physiology - Renal Physiology 296(3):F658 (2009)
Detrusor smooth muscle (DSM) hypertrophy induced by partial bladder outlet obstruction (PBOO) is associated with changes in the NH2-terminal myosin heavy chain isoform from predominantly SM-B to SM-A, alteration in the Ca2+ sensitization pathway, and the contractile characteristics from phasic t...
Ablation of smooth muscle myosin heavy chain SM2 increases smooth muscle contraction and results in postnatal death in mice.
PNAS 105(47):18614 (2008)
The physiological relevance of smooth muscle myosin isoforms SM1 and SM2 has not been understood. In this study we generated a mouse model specifically deficient in SM2 myosin isoform but expressing SM1, using an exon-specific gene targeting strategy. The SM2 homozygous knockout (SM2(-/-)) mice ...
Sarcoplasmic reticulum calcium uptake and speed of relaxation are depressed in nebulin-free skeletal muscle.
FASEB Journal 22(8):2912 (2008)
Previous work suggested that altered Ca(2+) homeostasis might contribute to dysfunction of nebulin-free muscle, as gene expression analysis revealed that the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)-inhibitor sarcolipin (SLN) is up-regulated >70-fold in nebulin knockout mice, and here ...
Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology.
Cardiovascular Research 77(2):265 (2008)
Cardiac sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA2a) plays a central role in myocardial contractility. SERCA2a actively transports Ca(2+) into the SR and regulates cytosolic Ca(2+) concentration, SR Ca(2+) load, and the rate of contraction and relaxation of the heart. In the heart, SERCA ...
Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility.
PNAS 104(45):17867 (2007)
Sarcolipin is a novel regulator of cardiac sarcoplasmic reticulum Ca2+ ATPase 2a (SERCA2a) and is expressed abundantly in atria. In this study we investigated the physiological significance of sarcolipin in the heart by generating a mouse model deficient for sarcolipin. The sarcolipin-null mice ...
Expression of SERCA isoform with faster Ca2+ transport properties improves postischemic cardiac function and Ca2+ handling and decreases myocardial infarction.
American Journal of Physiology - Heart and Circ... 293(4):H2418 (2007)
Myocardial ischemia-reperfusion (I/R) injury is associated with contractile dysfunction, arrhythmias, and myocyte death. Intracellular Ca(2+) overload with reduced activity of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) is a critical mechanism of this injury. Although upregulation of SERC...
Differential expression of sarcolipin protein during muscle development and cardiac pathophysiology.
Journal of Molecular and Cellular Cardiology 43(2):215 (2007)
Sarcolipin (SLN) is a small molecular weight sarcoplasmic reticulum (SR) membrane protein expressed both in cardiac and skeletal muscle tissues. Recent studies using transgenic mouse models have demonstrated that SLN is an important regulator of cardiac SR Ca2+ ATPase 2a (SERCA2a). However, ther...