Arization time of optical AP 7 / 15 Threonine 5 Modulates Sarcolipin Function Fig 4. Optical APs recorded from right atria of six-month old TG and NTG mice hearts. Representative traces recorded from the location points 14, respectively as indicated in the inset. The average upstroke period was indicated by the two vertical dashed lines in each panel. Summarized values of upstroke time and AP duration at 50 and 90 . indicates the significant difference between TG and NTG groups. doi:10.1371/journal.pone.0115822.g004 was significantly longer in the TG mice atria relative to NTG controls, implicating a slower AP propagation in the TG mice atria. Decreased Omtriptolide biological activity atrial contractility and diastolic dysfunction in the TG mice Echocardiographic measurements on the two-month old mice show that there were no significant differences in the LV end-diastolic dimension, LV end-systolic dimension, EF and FS between TG and NTG mice. However, the EF and FS were higher in the six-month old TG mice compared to those of age- and sex- matched NTG control mice. The diastolic septal wall thickness and systolic septal 
wall thickness were also increased in the TG mice, though these values were not statistically different from that of NTG control mice. Doppler echocardiography confirmed the enlargement of LA in six-month old TG mice. The atrial contraction velocity however was significantly reduced in both two- and six- month old TG mice. The reduced “A” velocity resulted in a 8 / 15 Threonine 5 Modulates Sarcolipin Function MK-0557 web DSEPWT-diastolic septal wall thickness; LVEDD- left ventricular end diastolic dimension; DPWT- diastolic posterior wall thickness; SSEPWT- systolic septal wall thickness; LVESD-Left ventricular end systolic dimension; SPWWT-systolic posterior wall thickness; EF-ejection fraction; FS-fractional shortening; HR- heart rate; bpm- beats per minute; LA Diameter- left atrial diameter; E velocity- early filling velocity; A velocity- atrial filling velocity. Data are mean SEM. significantly different from NTG, p<0.005 significantly different from NTG, p<0.05 n = 5 for 2 month old groups and n = 6 for 6 month old groups NTG vs.TG p = 0.056 doi:10.1371/journal.pone.0115822.t001 # significant increase in the ratio of transmitral flow velocity during early diastolic and atrial velocity, in the TG mice. We next examined how the transgenic expression of phosphorylation defective mutant SLN affects the hearts ability to respond to -adrenergic receptor stimulation. Results in Fig. 5 show that the NTG hearts responded to increasing doses of ISO with significant increase in frequency and contractility as shown by increased heart rate and EF. On the contrary, the TG hearts showed a significantly decreased ISO response in comparison to that of NTG controls. Furthermore in the TG mice, the basal HR and EF were significantly increased only after the highest dose of ISO infusion. Hemodynamic measurements on the TG mice show an increased LV end diastolic pressure and a decreased LV-dP/dt. The LV +dP/dt also decreased, but statistically not different. The expression and the activity of ubiquitin-proteasome components are increased in the TG mice hearts Several studies have suggested that the ubiquitin-proteasome system activation could contribute to the structural remodeling during cardiac pathology. PubMed ID:http://jpet.aspetjournals.org/content/120/3/269 We therefore determined if the cardiac structural remodeling is associated with the activation of UPS in the TG mice. Results in Fig. 6A show that the chymotrypsin-like acti.Arization time of optical AP 7 / 15 Threonine 5 Modulates Sarcolipin Function Fig 4. Optical APs recorded from right atria of six-month old TG and NTG mice hearts. Representative traces recorded from the location points 14, respectively as indicated in the inset. The average upstroke period was indicated by the two vertical dashed lines in each panel. Summarized values of upstroke time and AP duration at 50 and 90 . indicates the 
significant difference between TG and NTG groups. doi:10.1371/journal.pone.0115822.g004 was significantly longer in the TG mice atria relative to NTG controls, implicating a slower AP propagation in the TG mice atria. Decreased atrial contractility and diastolic dysfunction in the TG mice Echocardiographic measurements on the two-month old mice show that there were no significant differences in the LV end-diastolic dimension, LV end-systolic dimension, EF and FS between TG and NTG mice. However, the EF and FS were higher in the six-month old TG mice compared to those of age- and sex- matched NTG control mice. The diastolic septal wall thickness and systolic septal wall thickness were also increased in the TG mice, though these values were not statistically different from that of NTG control mice. Doppler echocardiography confirmed the enlargement of LA in six-month old TG mice. The atrial contraction velocity however was significantly reduced in both two- and six- month old TG mice. The reduced “A” velocity resulted in a 8 / 15 Threonine 5 Modulates Sarcolipin Function DSEPWT-diastolic septal wall thickness; LVEDD- left ventricular end diastolic dimension; DPWT- diastolic posterior wall thickness; SSEPWT- systolic septal wall thickness; LVESD-Left ventricular end systolic dimension; SPWWT-systolic posterior wall thickness; EF-ejection fraction; FS-fractional shortening; HR- heart rate; bpm- beats per minute; LA Diameter- left atrial diameter; E velocity- early filling velocity; A velocity- atrial filling velocity. Data are mean SEM. significantly different from NTG, p<0.005 significantly different from NTG, p<0.05 n = 5 for 2 month old groups and n = 6 for 6 month old groups NTG vs.TG p = 0.056 doi:10.1371/journal.pone.0115822.t001 # significant increase in the ratio of transmitral flow velocity during early diastolic and atrial velocity, in the TG mice. We next examined how the transgenic expression of phosphorylation defective mutant SLN affects the hearts ability to respond to -adrenergic receptor stimulation. Results in Fig. 5 show that the NTG hearts responded to increasing doses of ISO with significant increase in frequency and contractility as shown by increased heart rate and EF. On the contrary, the TG hearts showed a significantly decreased ISO response in comparison to that of NTG controls. Furthermore in the TG mice, the basal HR and EF were significantly increased only after the highest dose of ISO infusion. Hemodynamic measurements on the TG mice show an increased LV end diastolic pressure and a decreased LV-dP/dt. The LV +dP/dt also decreased, but statistically not different. The expression and the activity of ubiquitin-proteasome components are increased in the TG mice hearts Several studies have suggested that the ubiquitin-proteasome system activation could contribute to the structural remodeling during cardiac pathology. PubMed ID:http://jpet.aspetjournals.org/content/120/3/269 We therefore determined if the cardiac structural remodeling is associated with the activation of UPS in the TG mice. Results in Fig. 6A show that the chymotrypsin-like acti.
