Leptin Induces Hypertension and Endothelial Dysfunction via Aldosterone-Dependent Mechanisms in Obese Female Mice

Abstract

Obesity is a major risk factor for cardiovascular disease in males and females. Whether obesity triggers cardiovascular disease via similar mechanisms in both the sexes is, however, unknown. In males, the adipokine leptin highly contributes to obesity-related cardiovascular disease by increasing sympathetic activity. Females secrete 3× to 4× more leptin than males, but do not exhibit high sympathetic tone with obesity. Nevertheless, females show inappropriately high aldosterone levels that positively correlate with adiposity and blood pressure (BP). We hypothesized that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in females. Leptin control of the cardiovascular function was analyzed in female mice sensitized to leptin via the deletion of protein tyrosine phosphatase 1b (knockout) and in agouti yellow obese hyperleptinemic mice (Ay). Hypersensitivity to leptin (wild-type, 115 ± 2; protein tyrosine phosphatase 1b knockout, 124 ± 2 mm Hg; P<0.05) and obesity elevated BP (a/a, 113 ± 1; Ay, 128 ± 7 mm Hg; P<0.05) and impaired endothelial function. Chronic leptin receptor antagonism restored BP and endothelial function in protein tyrosine phosphatase 1b knockout and Ay mice. Hypersensitivity to leptin and obesity reduced BP response to ganglionic blockade in both strains and plasma catecholamine levels in protein tyrosine phosphatase 1b knockout mice. Hypersensitivity to leptin and obesity significantly increased plasma aldosterone levels and adrenal CYP11B2 expression. Chronic leptin receptor antagonism reduced aldosterone levels. Furthermore, chronic leptin and mineralocorticoid receptor blockade reduced BP and improved endothelial function in both leptin-sensitized and obese hyperleptinemic female mice. Together, these data demonstrate that leptin induces hypertension and endothelial dysfunction via aldosterone-dependent mechanisms in female mice and suggest that obesity leads to cardiovascular disease via sex-specific mechanisms.

Keywords: hypertension; leptin; mineralocorticoid receptor; obesity; sex.

Figure 1

Leptin sensitization and obesity increase blood pressure in female mice. Mean arterial pressure (MAP, A and B) and heat rate (HR, C and D) recorded in wild-type (WT) and protein tyrosine phosphatase 1b knockout (KO) mice as well as in lean (a/a) and agouti yellow obese (Ay) female mice treated or not with the leptin receptor antagonist Allo-Aca. Data are mean±SEM; n=6 to 8 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a, #P<0.05 vs KO or Ay.

Figure 2

Leptin sensitization and obesity induce endothelial dysfunction in female mice. Aortic ring relaxation to acetylcholine (ACh, A and B) and sodium nitroprusside (SNP, C and D) measured in wild-type (WT) and protein tyrosine phosphatase 1b knockout (KO) mice as well as in lean (a/a) and agouti yellow obese (Ay) female mice treated or not with the leptin receptor antagonist Allo-Aca. Data are mean±SEM; n=6 to 8 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a, #P<0.05 vs KO or Ay.

Figure 3

Leptin sensitization and obesity reduce neurogenic control of blood pressure. Blood pressure response to ganglionic blockade in (A) wild-type (WT) and leptin-sensitized (protein tyrosine phosphatase 1b knockout [KO]) mice as well as in (B) lean (a/a) and agouti yellow obese (Ay) female mice. Plasma (C and D) norepinephrine and (E and F) epinephrine levels. Data are mean±SEM; n=6 to 8 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a.

Figure 4

Leptin sensitization and obesity increase aldosterone signaling. Plasma aldosterone levels measured in (A) wild-type (WT) and protein tyrosine phosphatase 1b knockout (KO) mice as well as in (B) lean (a/a) and agouti yellow obese (Ay) female mice treated or not with the leptin receptor antagonist Allo-Aca. C and D, Representative Western blot image for CYP11B2 and β-actin. E and F, Quantification of the Western blot for CYP11B2. Data are mean±SEM; n=6 to 12 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a, #P<0.05 vs KO or Ay.

Figure 5

Leptin sensitization and obesity elevate blood pressure via mineralocorticoid receptor (MR)–dependent mechanisms. Mean arterial pressure (MAP, A and B) and heat rate (HR, C and D) recorded in wild-type (WT) and protein tyrosine phosphatase 1b knockout (KO) mice as well as in lean (a/a) and agouti yellow obese (Ay) female mice treated or not with the MR blocker spironolactone (spiro). Data are mean±SEM; n=6 to 8 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a, #P<0.05 vs KO or Ay.

Figure 6

Leptin sensitization and obesity impair endothelial function via mineralocorticoid receptor (MR)–dependent mechanisms. Aortic ring relaxation to acetylcholine (ACh, A and B) and sodium nitroprusside (SNP, C and D) measured in wild-type (WT) and protein tyrosine phosphatase 1b knockout (KO) mice as well as in lean (a/a) and agouti yellow obese (Ay) female mice treated or not with the MR blocker spironolactone (spiro). Data are mean±SEM; n=6 to 8 for WT and KO mice and n=3 for a/a and Ay mice. *P<0.05 vs WT or a/a, #P<0.05 vs KO or Ay.