Sodium pump inhibitors in blood pressure regulation and in profibrotic signaling in salt sensitive hypertension and aging

National Institute On Aging

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Abstract

Two pro-fibrotic pathways, Fli1-dependent and TGF-beta-dependent, are activated by MBG in the animal models, and in the cultured rat vascular smooth muscle cells and cardiac myocytes. The TGF-beta-dependent pathway is activated by heightened MBG in the presence of a high salt intake in cardiovascular and renal tissues from hypertensive Dahl salt-sensitive rats and normotensive Sprague-Dawley rats. We demonstrated (i) that Fli1-dependent and TGF-beta-dependent pro-fibrotic pathways exhibit a crosstalk at the level of phosphorylated PKC-delta, (ii) that these pathways are activated either independently, or simultaneously, and (iii) that the activation of the profibrotic signaling is blood pressure independent. Experiment 1. The clinical study included data of 711 participants (black participants 51%, men 42%, mean age 24.8 +/- 3.0 years). We measured the carotid-femoral pulse wave velocity (cfPWV), 24-h urinary MBG and sodium excretion. In single, partial and multivariable adjusted regression analyses, we found a persistent positive association between cfPWV and MBG excretion in young women, but not men. Multiple regression models were adjusted for ethnicity, age, waist-to-height ratio, mean arterial BP, high-density lipoprotein cholesterol, C-reactive protein, glutamyl transferase and glucose. In conclusion, already at a young age heightened endogenous MBG levels may contribute to large artery stiffness in women via pressure-independent mechanisms, increasing their risk for future cardiovascular disease. Recent findings demonstrated that 24-hour urinary MBG strongly associates with habitual salt intake in young healthy adults (aged 20-30 years). Furthermore, in young healthy adults free of detected cardiovascular disease, MBG associates with increased large artery stiffness and left ventricular mass independent of blood pressure. These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy. Twenty-four-hour urinary MBG may be a potential biomarker of early cardiovascular risk. Adverse associations between MBG, which increases with salt consumption, and early cardiovascular risk markers support the global efforts to reduce population-wide salt intake in an effort to prevent and control the burden of non-communicable diseases. Conclusion: These findings in human studies corroborate mechanistic data from rat studies whereby stimulation of MBG by a high salt intake or MBG infusion increased vascular fibrosis and cardiac hypertrophy. MBG is a marker of salt-sensitivity and may be a potential biomarker of early cardiovascular risk. Experiment 2. Hypertensive response in Dahl Salt-Sensitive rats (DSS) on a high salt (HS) diet is accompanied by central arterial stiffening (CAS) and heightened levels of an endogenous Na/K-ATPase inhibitor, marinobufagenin (MBG), a pro-hypertensive and profibrotic factor. CAS is a risk factor for dementia. We studied the effect of the in vivo administration of MBG or HS diet on blood pressure, CAS and behavioral function in young DSS and normotensive Sprague-Dawley rats (SD), a genetic background for DSS. Eight weeks old male SD and DSS were given HS diet (8% NaCl; n=18/group), or low salt diet (LS; 0.1% NaCl; n=14-18/group) for 8 weeks, or MBG (n=15-18/group) administered via osmotic minipumps for 4 weeks. The MBG-treated groups received LS diet. Systolic blood pressure (SBP), pulse wave velocity (PWV), a marker of CAS, MBG, Morris water maze (MWM) test to measure spatial memory and the tissue collection for the histochemical analysis were assessed at the end of the experiment. DSS-LS had higher SBP and PWV and worst spatial memory than SD-LS. The administration of stressors, HS and MBG, increased PWV, SBP and aortic wall collagen abundance in both strains vs. their LS controls. In SD, HS and MBG administration did not affect heart parameters, assessed by echocardiography (ECHO), vs. SD-LS control, where as in DSS, the impaired whole-heart structure and function were observed after HS diet in DSS-HS vs. DSS-LS. MBG treatment did not affect the ECHO parameters in DSS-MBG vs. DSS-LS. HS diet led to increase of an endogenous plasma and urine MBG in both SD and DSS. Thus, the pro-hypertensive and profibrotic effect of HS can be at least partially attributed to MBG increase. The pro-hypertensive and profibrotic functions of MBG were pronounced in both DSS and SD, although quantitative PCR revealed different profiles of profibrotic genes in DSS and SD activated by MBG or HS. Spatial memory was not affected by HS diet or MBG treatment not in SD, nor in DSS. Conclusions: Overall higher blood pressure, CAS and cardiovascular remodeling may underlie the impaired cognitive functions in young DSS-LS in comparison to young SD-LS. MBG and HS had near similar effects on cardiovascular system and function in DSS and SD rats, although the rate of changes vs. control in SD was lower than that in DSS rats. The absence of the cumulative effect of the increased PWV and blood pressure on spatial memory can be explained by the brain plasticity in young rats, which helped the animals to sustain the elevated CAS and to counterbalance the profibrotic effects of MBG.