The brain Renin-Angiotensin system and mitochondrial function: influence on blood pressure and baroreflex in transgenic rat strains

Abstract

Mitochondrial dysfunction is implicated in many cardiovascular diseases, including hypertension, and may be associated with an overactive renin-angiotensin system (RAS). Angiotensin (Ang) II, a potent vasoconstrictor hormone of the RAS, also impairs baroreflex and mitochondrial function. Most deleterious cardiovascular actions of Ang II are thought to be mediated by NADPH-oxidase- (NOX-) derived reactive oxygen species (ROS) that may also stimulate mitochondrial oxidant release and alter redox-sensitive signaling pathways in the brain. Within the RAS, the actions of Ang II are counterbalanced by Ang-(1-7), a vasodilatory peptide known to mitigate against increased oxidant stress. A balance between Ang II and Ang-(1-7) within the brain dorsal medulla contributes to maintenance of normal blood pressure and proper functioning of the arterial baroreceptor reflex for control of heart rate. We propose that Ang-(1-7) may negatively regulate the redox signaling pathways activated by Ang II to maintain normal blood pressure, baroreflex, and mitochondrial function through attenuating ROS (NOX-generated and/or mitochondrial).

Figure 1

Proposed model: Ang-(1–7) through indirect (NADPH oxidase-mediated ROS) and/or direct interactions with mitochondria can attenuate ROS in dorsal medulla resulting in reduced blood pressure and enhanced baroreflex and mitochondrial function. ROS: reactive oxygen species; MAP: mean arterial pressure; BRS: baroreflex sensitivity; MF: Mitochondrial function; ?: not known.

Figure 2

Major characteristics of (mRen2)27, Sprague-Dawley (SD), and ASrAOGEN rat strains with respect to hemodynamic and baroreflex function. AOGEN: angiotensinogen, BRS: baroreflex sensitivity, RAS: renin-angiotensin system.

Figure 3

ASrAOGEN (AS) rats show significantly greater reduction in the evoked BRS for control of HR following inhibition of PTP1b (a), despite similar levels of the PTP1b protein in dorsal medulla of the three strains (b). Mean ± SEM (n = 4–6 per group for solitary tract nucleus (NTS) microinjections, n = 6 for Western blotting); *P < 0.05 versus (mRen2)27 rats. Data replotted from [23] for the Sprague-Dawley (SD) rats and original data presented for ASrAOGEN and (mRen2)27 [mRen] rats. Western blotting carried out as published for SD rats [23] and original data presented for ASrAOGEN and (mRen2)27 rats. Note the PTP1b antibody recognizes both phosphorylated and nonphosphorylated forms.

Figure 4

Hypertensive (mRen2)27 rats show significantly increased phosphorylated AMP-Kinase (AMPK) in the brain dorsal medulla. AMPK-α (a) and β ₁ (b) activities were measured by Western blot hybridization using phospho-specific antibodies (Cell Signaling) in brain dorsal medulla tissues from (mRen2)27 [mRen], Sprague-Dawley (SD), and ASrAOGEN (AS) rats. Top: Densitometry analyses of phoshorylated protein levels normalized to total AMPK-α and β ₁/β ₂; bottom: representative Western blots. Data are mean ± SEM (n = 3–6 per group); *P < 0.05 versus SD; ^† P < 0.05 versus AS rats.

Figure 5

Brain dorsal medullary ATP levels (a) and mitochondrial content as measured using citrate synthase (b) was not different among hypertensive (mRen2)27 [mRen], Sprague-Dawley (SD) or hypotensive ASrAOGEN (AS) rats. ATP levels were determined using a chemiluminescent assay (Promega) and citrate synthase activity was measured using the assay kit (Sigma) in tissue homogenates. Mean ± SEM (n = 6 per group).