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Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice.

Lai NC, Gao MH, Giamouridis D, Suarez J, Miyanohara A, Parikh J, Hightower S, Guo T, Dillmann W, Kim YC, Diaz-Juarez J, Hammond HK - Hum. Gene Ther. (2015)

Bottom Line: UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and rate of Ca(2+) decline and increased SERCA2a expression.We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart.The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.

View Article: PubMed Central - PubMed

Affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.

ABSTRACT
Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, is costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. We previously showed that a single intravenous (IV) injection of AAV8.UCn2 increases plasma UCn2 and left ventricular (LV) systolic and diastolic function for at least 7 months in normal mice. Here we test the hypothesis that IV delivery of AAV8.UCn2 increases function of the failing heart. Myocardial infarction (MI, by coronary ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) <25% received IV delivery of AAV8.UCn2 (5×10(11) gc) or saline, and 5 weeks later echocardiography showed increased LV EF in mice that received UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in peak rate of LV pressure development (LV +dP/dt; p<0.0001) and a 1.6-fold increase in peak rate of LV pressure decay (LV -dP/dt; p=0.0007), indicating increased LV systolic and diastolic function in treated mice. UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and rate of Ca(2+) decline and increased SERCA2a expression. In addition, UCn2 gene transfer reduced Thr286 phosphorylation of Cam kinase II, and increased expression of cardiac myosin light chain kinase, findings that would be anticipated to increase function of the failing heart. We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart. The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.

No MeSH data available.


Related in: MedlinePlus

LV function in vivo. (A and B) Five weeks after AAV8.UCn2 (5×1011 gc, IV) or saline (HF) infusion, in vivo studies were performed to measure the rate of LV pressure development: LV +dP/dt (A) and decay LV −dP/dt (B). AAV8.UCn2 increased LV +dP/dt and LV −dP/dt 5 weeks after gene transfer, indicating that UCn2 gene transfer increases LV systolic function. (C and D) Heart rate tended to be higher (D). LV-developed pressure was increased by UCn2 gene transfer (C). Studies were performed without knowledge of group identity. p-Values are from Student's t-test (unpaired, 2-tailed). Data represent mean±SE, and numbers in bars denote group size.
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f2: LV function in vivo. (A and B) Five weeks after AAV8.UCn2 (5×1011 gc, IV) or saline (HF) infusion, in vivo studies were performed to measure the rate of LV pressure development: LV +dP/dt (A) and decay LV −dP/dt (B). AAV8.UCn2 increased LV +dP/dt and LV −dP/dt 5 weeks after gene transfer, indicating that UCn2 gene transfer increases LV systolic function. (C and D) Heart rate tended to be higher (D). LV-developed pressure was increased by UCn2 gene transfer (C). Studies were performed without knowledge of group identity. p-Values are from Student's t-test (unpaired, 2-tailed). Data represent mean±SE, and numbers in bars denote group size.

Mentions: In vivo assessment of LV pressure development showed substantial increases in rates of LV pressure development (LV +dP/dt; p<0.0001) and in LV relaxation (LV −dP/dt; p<0.0007) (Fig. 2 and Table 4). There were no group differences in mean arterial pressure (Table 4). Heart rate during these studies, conducted under anesthesia, was somewhat higher in mice that had received UCn2 gene transfer, but the difference did not reach statistical significance.


Intravenous AAV8 Encoding Urocortin-2 Increases Function of the Failing Heart in Mice.

Lai NC, Gao MH, Giamouridis D, Suarez J, Miyanohara A, Parikh J, Hightower S, Guo T, Dillmann W, Kim YC, Diaz-Juarez J, Hammond HK - Hum. Gene Ther. (2015)

LV function in vivo. (A and B) Five weeks after AAV8.UCn2 (5×1011 gc, IV) or saline (HF) infusion, in vivo studies were performed to measure the rate of LV pressure development: LV +dP/dt (A) and decay LV −dP/dt (B). AAV8.UCn2 increased LV +dP/dt and LV −dP/dt 5 weeks after gene transfer, indicating that UCn2 gene transfer increases LV systolic function. (C and D) Heart rate tended to be higher (D). LV-developed pressure was increased by UCn2 gene transfer (C). Studies were performed without knowledge of group identity. p-Values are from Student's t-test (unpaired, 2-tailed). Data represent mean±SE, and numbers in bars denote group size.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4492611&req=5

f2: LV function in vivo. (A and B) Five weeks after AAV8.UCn2 (5×1011 gc, IV) or saline (HF) infusion, in vivo studies were performed to measure the rate of LV pressure development: LV +dP/dt (A) and decay LV −dP/dt (B). AAV8.UCn2 increased LV +dP/dt and LV −dP/dt 5 weeks after gene transfer, indicating that UCn2 gene transfer increases LV systolic function. (C and D) Heart rate tended to be higher (D). LV-developed pressure was increased by UCn2 gene transfer (C). Studies were performed without knowledge of group identity. p-Values are from Student's t-test (unpaired, 2-tailed). Data represent mean±SE, and numbers in bars denote group size.
Mentions: In vivo assessment of LV pressure development showed substantial increases in rates of LV pressure development (LV +dP/dt; p<0.0001) and in LV relaxation (LV −dP/dt; p<0.0007) (Fig. 2 and Table 4). There were no group differences in mean arterial pressure (Table 4). Heart rate during these studies, conducted under anesthesia, was somewhat higher in mice that had received UCn2 gene transfer, but the difference did not reach statistical significance.

Bottom Line: UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and rate of Ca(2+) decline and increased SERCA2a expression.We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart.The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.

View Article: PubMed Central - PubMed

Affiliation: 1 VA San Diego Healthcare System , San Diego, CA 92161.

ABSTRACT
Urocortin-2 (UCn2) peptide infusion increases cardiac function in patients with heart failure, but chronic peptide infusion is cumbersome, is costly, and provides only short-term benefits. Gene transfer would circumvent these shortcomings. We previously showed that a single intravenous (IV) injection of AAV8.UCn2 increases plasma UCn2 and left ventricular (LV) systolic and diastolic function for at least 7 months in normal mice. Here we test the hypothesis that IV delivery of AAV8.UCn2 increases function of the failing heart. Myocardial infarction (MI, by coronary ligation) was used to induce heart failure, which was assessed by echocardiography 3 weeks after MI. Mice with LV ejection fraction (EF) <25% received IV delivery of AAV8.UCn2 (5×10(11) gc) or saline, and 5 weeks later echocardiography showed increased LV EF in mice that received UCn2 gene transfer (p=0.01). In vivo physiological studies showed a 2-fold increase in peak rate of LV pressure development (LV +dP/dt; p<0.0001) and a 1.6-fold increase in peak rate of LV pressure decay (LV -dP/dt; p=0.0007), indicating increased LV systolic and diastolic function in treated mice. UCn2 gene transfer was associated with increased peak systolic Ca(2+) transient amplitude and rate of Ca(2+) decline and increased SERCA2a expression. In addition, UCn2 gene transfer reduced Thr286 phosphorylation of Cam kinase II, and increased expression of cardiac myosin light chain kinase, findings that would be anticipated to increase function of the failing heart. We conclude that a single IV injection of AAV8.UCn2 increases function of the failing heart. The simplicity of IV injection of a vector encoding a gene with beneficial paracrine effects to increase cardiac function is an attractive potential clinical strategy.

No MeSH data available.


Related in: MedlinePlus