The urotensin II receptor antagonist DS37001789 ameliorates mortality in pressure-overload mice with heart failure

Figures

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  Figure 1. Chemical structure of DS37001789.

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  Figure 2. Effect of DS37001789 on mortality in pressure-overload mice. Kaplan–Meier survival plot of 12-week-old mice after the transverse aortic constriction (TAC) surgery. The survival rates of vehicle-treated sham-operated mice (Sham, n = 5), vehicle-treated TAC mice (Vehicle, n = 37), 0.06% DS37001789-treated TAC mice (DS37001789 0.06%, n = 32), and 0.2% DS37001789-treated TAC mice (DS37001789 0.2%, n = 32) are shown. *P < 0.05, significantly different from the vehicle-treated control group.

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  Figure 3. Effects of DS37001789 on hemodynamic parameters in pressure-overload mice. (A) Hemodynamic parameters of heart rate (HR), (B) left ventricular pressure (LVP), (C) left ventricular end-diastolic volume (LVEDV), (D) left ventricular end-systolic volume (LVESV), and (E) ejection fraction (EF) after 4-week administration of vehicle or DS37001789. Vehicle-treated sham-operated mice (Sham, n = 4), vehicle-treated transverse aortic constriction-induced pressure overload mice (TAC) (Vehicle, n = 4), 0.06% DS37001789-treated TAC mice (n = 4), and 0.2% DS37001789-treated TAC mice (n = 4) were measured. Data are expressed as mean ± S.E.M. *P < 0.05, significantly different from the sham-operated mice group; #P < 0.05, significantly different from the TAC vehicle-treated control group.

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  Figure 4. Effects of DS37001789 on echocardiographic parameters in pressure-overload mice. Echocardiographic parameters of (A) ejection fractions (EFs), (B) left ventricular end-diastric diameter (LVDd), and (C) left ventricular end-systolic diameter (LVDs) 1 week after the transverse aortic constriction (TAC) surgery and after 4 weeks of administration of vehicle or DS37001789. Vehicle-treated sham-operated mice (Sham, n = 3), vehicle-treated transverse aortic constriction-induced pressure-overload mice (TAC) (Vehicle, n = 11), 0.06% DS37001789-treated TAC mice (n = 7), and 0.2% DS37001789-treated TAC mice (n = 10) were measured. Data are expressed as mean ± S.E.M.

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  Figure 5. Effects of DS37001789 on tissue weight in pressure-overload mice. (A) Left ventricular weight/body weight, and (B) lung weight/body weight after 4 weeks of administration in pressure-overload mice. Vehicle-treated sham-operated mice (Sham, n = 8), vehicle-treated transverse aortic constriction-induced pressure-overload mice (TAC) (Vehicle, n = 15), 0.06% DS37001789-treated TAC mice (n = 10), and 0.2% DS37001789-treated TAC mice (n = 10) were measured. Data are expressed as mean ± S.E.M. *P < 0.05, significantly different from the sham-operated mouse group.

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  Figure 6. Effects of DS37001789 on mRNA expression in pressure-overload mice. (A) Atrial natriuretic peptide (ANP), (B) brain natriuretic peptide (BNP), (C) sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), (D) phospholamban (PLN), (E) regulator of calcineurin 1 (RCAN-1), and (F) collagen type I alpha 2 (COL1A2) expression after 4 weeks of administration in pressure-overload mice. mRNA expression levels of ANP, BNP, SERCA2a, PLB, RCAN-1, and COL1A2 normalized to Gapdh levels in vehicle-treated sham-operated mice (Sham, n = 3), vehicle-treated transverse aortic constriction-induced pressure-overload mice (TAC) (Vehicle, n = 4), 0.06% DS37001789-treated TAC mice (n = 3), and 0.2% DS37001789-treated TAC mice (n = 3) were measured. Data are expressed as mean ± S.E.M. *P < 0.05, significantly different from the sham-operated mouse group; #P < 0.05, significantly different from the TAC vehicle-treated control group.

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  Figure 7. Effect of cardiac GPR14 expression on DS37001789 and plasma concentrations of DS37001789 after 4 weeks of administration in pressure-overload mice. (A) GPR14 expression in left ventricle by western blot analysis. GPR14 expression levels normalized to GAPDH levels in vehicle-treated sham-operated mice (Sham, n = 3), vehicle-treated transverse aortic constriction-induced pressure-overload mice (TAC) (Vehicle, n = 4), and 0.2% DS37001789-treated TAC mice (n = 3) were measured. Data are expressed as mean ± S.E.M. (B) GPR14 expression in rat isolated cardiomyocyte by western blot analysis. GPR14 expression levels normalized to GAPDH levels. (C) Plasma compound concentrations in 0.06% DS37001789-treated TAC mice (n = 6) and 0.2% DS37001789-treated TAC mice (n = 10) were measured. Data are expressed as mean ± S.E.M. The full, uncropped versions of the blots can be found as supplementary materials.

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  Figure 8. Mortality after pressure overload in GPR14 knockout (KO) mice. Kaplan–Meier survival plot of 5-week-old mice after the transverse aortic constriction (TAC) surgery. The survival rates of sham-operated wild-type (WT) mice (Sham + WT, n = 14), sham-operated GPR14 KO mice (Sham + GPR14 KO, n = 13), TAC-operated WT mice (TAC + WT, n = 63), and TAC-operated GPR14 KO mice (TAC + GPR14KO, n = 40) are shown. *P < 0.05, significantly different from the TAC WT group.

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  Figure 9. Effect of GPR14 knockout (KO) on echocardiographic parameters in pressure-overload mice. Echocardiographic parameters of (A) ejection fractions (EFs), (B) left ventricular end-diastoric diameter (LVDd), and (C) left ventricular end-systolic diameter (LVDs) at 1 and 4 weeks after the transverse aortic constriction (TAC) surgery. The results of sham-operated WT mice (Sham + WT, n = 10), sham-operated GPR14 KO mice (Sham + GPR14KO, n = 8), TAC-operated WT mice (TAC + WT, n = 35), and TAC-operated GPR14KO mice (TAC + GPR14KO, n = 30) are shown. Data are expressed as mean ± S.E.M. *P < 0.05, significantly different from the TAC WT group.

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  Figure 10. Effects of GPR14 knockout (KO) on tissue weight 4 weeks after the transverse aortic constriction (TAC) surgery. (A) Left ventricular weight/body weight and (B) lung weight/body. Results of sham-operated WT mice (n = 4), sham-operated GPR14 KO mice (n = 4), TAC-operated WT mice (n = 12), and TAC-operated GPR14 KO mice (n = 9) are shown. Data are expressed as mean ± S.E.M. *P < 0.05, significantly different from the sham WT group. $P < 0.05, significantly different from the sham GPR14 KO group.