A Sex-Specific Role of Endothelial Sirtuin 3 on Blood Pressure and Diastolic Dysfunction in Female Mice

Figures

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  Figure 1. Loss of endothelial SIRT3 elevates blood pressure and impairs diastolic function in the female mice. (A,B) Mean arterial blood pressure (MAP) and systolic blood pressure (SBP) are elevated in the female endothelial-specific SIRT3 knockout (SIRT3 ECKO) mice when compared to SIRT3 LoxP mice. N = 14–15 mice. (C,D) Isovolumic relaxation time (IVRT) and myocardial performance index (MPI) are increased in the female SIRT3 ECKO mice when compared to SIRT3LoxP mice. (E) The E’/A’ ratio is decreased in the female SIRT3 ECKO mice when compared to SIRT3LoxP mice. N = 7–8 mice. * p < 0.05 vs. SIRT3 LoxP.

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  Figure 2. The role of endothelial SIRT3 deficiency on sex differences. (A,B) MAP and SBP are elevated in both male and female SIRT3 ECKO mice when compared to the corresponding SIRT3LoxP mice. However, female SIRT3 ECKO mice have higher blood pressure than the male mice. N = 13–18 mice. (C) IVRT is increased in the female SIRT3 ECKO mice when compared to the female SIRT3LoxP and male SIRT3 ECKO mice. N = 7–9 mice. (D) The arterial stiffness is significantly increased in both male and female SIRT3 ECKO mice when compared to the corresponding SIRT3LoxP mice. Female SIRT3 ECKO mice have similar pulse wave velocity (PWV) as the male SIRT3 ECKO mice. N = 5–11 mice. * p < 0.05.

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  Figure 3. High-fat-diet (HFD)-induced obesity, cardiac, and lung growth. (A,C) HFD induced a significant increase in the body weight and percentage of adipose tissue in both SIRT3 LoxP and SIRT3 ECKO mice. (B) HFD induced cardiac hypertrophy only in female SIRT3 ECKO mice as evidenced by the increased heart weight (HW)/tibia length ratio. (D) By contrast, HFD caused increased lung growth only in female SIRT3 LoxP mice. N = 7–10 mice. * p < 0.05 vs. SIRT3 LoxP+normal diet (ND); # p < 0.05 vs. SIRT3 ECKO+ND; † p < 0.05 vs. SIRT3 LoxP+HFD. (E) Quantification of area under curve (AUC) for glucose tolerance test (GTT) in male SIRT3-Loxp mice and SIRT3 ECKO mice fed a ND or HFD (N = 8–10 mice). **** p < 0.0001. (F) Quantification of area under curve for glucose tolerance test in male and female SIRT3-Loxp mice and SIRT3 ECKO mice fed a ND or HFD (N = 7–9 mice). *** p < 0.001, **** p < 0.0001.

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  Figure 4. Loss of endothelial SIRT3 exacerbates HFD-induced changes in hemodynamics and diastolic function. (A,B) HFD results in a significant increase in the MAP and SBP in the female SIRT3 LoxP mice when compared to the ND-fed control mice. HFD does not further increase the blood pressure in the female SIRT3 ECKO mice. N = 5 mice. * p < 0.05 (C) HFD further prolongs the IVRT when compared to the SIRT3 LoxP mice fed a ND. * p <0.05 (D) HFD does not alter the MPI in either SIRT3 LoxP or SIRT3 ECKO mice. * p <0.05 (E) HFD leads to a significant decrease in the E’/A’ ratio in the female SIRT3 LoxP mice when compared to the ND-fed control mice, but HFD does not decrease the E’/A’ ratio in the female SIRT3 ECKO mice. N = 7–9 mice. * p < 0.05. (F) HFD does not significantly decrease the coronary flow reserve (CFR). N = 6–9 mice. (G) The ejection fraction (E,F) was not different between the female SIRT3 LoxP and SIRT3 ECKO mice when fed either ND or HFD. N = 7–9 mice.

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  Figure 5. The role of endothelial SIRT3 deficiency on sex differences in HFD-induced cardiovascular dysfunction. (A,B) HFD increases the blood pressure in both male and female control SIRT3 LoxP mice. (C,D) HFD does not further increase blood pressure in female SIRT3 ECKO mice as observed in the male SIRT3 ECKO mice. N = 5 mice. * p < 0.05 (E,F) Female SIRT3 ECKO mice fed an HFD exhibit impaired CFR and diastolic dysfunction when compared to the female SIRT3LoxP mice. The HFD decreases CFR and increases IVRT in the female SIRT3 ECKO mice but not in the male SIRT3 ECKO mice fed an HFD. N = 8–9 mice. * p < 0.05