Small artery remodeling and stiffening in deoxycorticosterone acetate-salt hypertensive rats involves the interaction between endogenous ouabain/Na + K + -ATPase/cSrc signaling.

OBJECTIVE: Endogenous ouabain (EO) increases in some patients with hypertension and in rats with volume-dependent hypertension. When ouabain binds to Na + K + -ATPase, cSrc is activated, which leads to multieffector signaling activation and high blood pressure (BP). In mesenteric resistance arteries (MRA) from deoxycorticosterone acetate (DOCA)-salt rats, we have demonstrated that the EO antagonist rostafuroxin blocks downstream cSrc activation, enhancing endothelial function and lowering oxidative stress and BP. Here, we examined the possibility that EO is involved in the structural and mechanical alterations that occur in MRA from DOCA-salt rats. METHODS: MRA were taken from control, vehicle-treated DOCA-salt or rostafuroxin (1 mg/kg per day, for 3 weeks)-treated DOCA-salt rats. Pressure myography and histology were used to evaluate the mechanics and structure of the MRA, and western blotting to assess protein expression. RESULTS: DOCA-salt MRA exhibited signs of inward hypertrophic remodeling and increased stiffness, with a higher wall:lumen ratio, which were reduced by rostafuroxin treatment. The enhanced type I collagen, TGFß1, pSmad2/3 Ser465/457 /Smad2/3 ratio, CTGF, p-Src Tyr418 , EGFR, c-Raf, ERK1/2 and p38MAPK protein expression in DOCA-salt MRA were all recovered by rostafuroxin. CONCLUSION: A process combining Na + K + -ATPase/cSrc/EGFR/Raf/ERK1/2/p38MAPK activation and a Na + K + -ATPase/cSrc/TGF-1/Smad2/3/CTGF-dependent mechanism explains how EO contributes to small artery inward hypertrophic remodeling and stiffening in DOCA-salt rats. This result supports the significance of EO as a key mediator for end-organ damage in volume-dependent hypertension and the efficacy of rostafuroxin in avoiding remodeling and stiffening of small arteries.

MMP inhibition attenuates hypertensive eccentric cardiac hypertrophy and dysfunction by preserving troponin I and dystrophin.

PURPOSE: Cardiac transition from concentric (C-LVH) to eccentric left ventricle hypertrophy (E-LVH) is a maladaptive response of hypertension. Matrix metalloproteinases (MMPs), in particular MMP-2, may contribute to tissue remodeling by proteolyzing extra- and intracellular proteins. Troponin I and dystrophin are two potential targets of MMP-2 examined in this study and their proteolysis would impair cardiac contractile function. We hypothesized that MMP-2 contributes to the decrease in troponin I and dystrophin in the hypertensive heart and thereby controls the transition from C-LVH to E-LVH and cardiac dysfunction. METHODS: Male Wistar rats were divided into sham or two kidney-1 clip (2K-1C) hypertensive groups and treated with water (vehicle) or doxycycline (MMP inhibitor, 15 mg/kg/day) by gavage from the tenth to the sixteenth week post-surgery. Tail-cuff plethysmography, echocardiography, gelatin zymography, confocal microscopy, western blot, mass spectrometry, in silico protein analysis and immunofluorescence were performed. RESULTS: 6 out of 23 2K-1C rats (26%) had E-LVH followed by reduced ejection fraction. The remaining had C-LVH with preserved cardiac function. Doxycycline prevented the transition from C-LVH to E-LVH. MMP activity is increased in C-LVH and E-LVH hearts which was inhibited by doxycycline. This effect was associated with an increase in troponin I cleavage products and a decline in dystrophin in the left ventricle of E-LVH rats, which was prevented by doxycycline. CONCLUSION: Hypertension causes increased cardiac MMP-2 activity which proteolyzes troponin I and dystrophin, contributing to the transition from C-LVH to E-LVH and cardiac dysfunction.

Reduced levels of potential circulating biomarkers of cardiovascular diseases in apparently healthy vegetarian men.

BACKGROUND: Several evidences report that a vegetarian diet is protector against cardiovascular diseases. Few studies have demonstrated the circulating profile of cardiovascular biomarkers in vegetarians. Therefore, the aims of the current study were compared the plasma concentrations of myeloperoxidase (MPO), metalloproteinase (MMP)-9, MMP-2, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 between healthy vegetarian (Veg) and healthy omnivorous (Omn). METHODS: Using ELISA and multiplexed bead immunoassay, we measured in plasma from 43 Veg and 41 Omn the cardiovascular biomarkers concentrations cited above. RESULTS: We found significant lower concentrations of MPO, MMP-9, MMP-2 and MMP-9/TIMP-1 ratio in Veg compared to Omn (all P<0.05). Moreover, MMP-9 concentrations were correlated positively with leukocytes and neutrophils count in both groups (all P<0.05). CONCLUSION: A vegetarian diet is associated with a healthier profile of cardiovascular biomarkers compared to omnivorous.