RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans

Abstract

RhoA/Rho-kinase signaling and its relationship/balance with the nitric oxide level, angiotensin II and vasopressors for cardiovascular pathophysiology is of increasing importance, and its involvement goes far beyond blood pressure regulation. The deep involvement of this pathway in cardiovascular biology is now known to include a wide spectrum of conditions relating to the long-term complications of hypertension, and in general of cardiovascular pathophysiology, such as changes in cardiovascular structure (remodeling) and the induction of atherosclerosis, involvement in the pathophysiological relationships between inflammation and hypertension, and in those between hypertension, glucose metabolism and insulin resistance. Studies from our laboratory have made an important contribution to the understanding of the cellular and molecular mechanisms mediated by the RhoA/Rho-kinase pathway, which include all the aspects of cardiovascular pathophysiology in which this pathway plays a role. In addition, if it is considered that our contribution to the clarification of these mechanisms only comes from studies in humans, their impact on the scenario of the RhoA/Rho-kinase pathway's biology, essentially supported by studies 'in vitro' or in animal models, is immediate. This review examines all the aspects of RhoA/Rho-kinase signaling in the light of the available data, and gives an updated and useful overall picture of its involvement in cardiovascular pathophysiology.

Angiotensin II Activates the RhoA Exchange Factor Arhgef1 in Humans

“…Only study in leukocytes from patients with Bartter and Gitelman syndromes has indirectly suggested a role of Arhgef1 and Rho kinase signaling pathway in the Ang II effect in humans. 24,25 Our results confirm that Arhgef1 is expressed in human PBMC and activated RhoA/Rho kinase signaling in response to Ang II stimulation in vitro. They further show that Arhgef1 activity and RhoA/Rho kinase signaling are increased by the physiological activation of the RAS.…”

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

“…For example, one could speculate that CD34+KDR+ cell phenotype may correlate with pathological vascular damage and increased CV risk, 48 while CD133+KDR+ and CD34+CD133+KDR+ are likely related to oxidative status and endothelial function as suggested by their status in BS/GS that is, increased CD133+KDR+ and CD34+CD133+KDR+ and unchanged CD34+KDR+, which fits with the biochemical, molecular and functional picture of good endothelial status reported in these patients. [16][17][18][19][20][21][22][23][26][27][28] In conclusion, the study documents in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in CV status. These results alongside the ongoing studies in our laboratory to quantitate calcitonin gene-related peptide and EPC status for example, senescence and proliferation in BS/GS, reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of CV remodeling in humans.…”

“…15 The results of an extensive series of studies from our laboratory have provided mechanistic explanations for these patients' vascular hyporeactivity and absence of CV remodeling. [16][17][18][19][20] We have documented a blunted Ang II signaling and related pathways [21][22][23][24][25][26][27][28] in BS/GS patients. In addition, we have reported in BS/GS reduced oxidative stress alongside increased HO-1 gene expression, 29,30 upregulation of nitric oxide (NO) system 31,32 and increased NO-dependent vasodilation.…”

“…19 BS/GS likely represents a human model of endogenous Ang II type 1 receptor antagonism and produce a mirror image of the alterations found in hypertension. [16][17][18][19][20] Given these characteristics, the BS/GS model represents a useful system to further investigate the relationship of EPCs dysfunction with the pathogenesis of hypertensive CV end organ damage.…”

Linking inflammation and hypertension in humans: studies in Bartter's/Gitelman's syndrome patients

“…5,6 In BS/GS, we have demonstrated that the Ang II signalling pathway is blunted as documented by the increased regulator of G-protein signalling-2 gene and protein expression, reduced gene and protein expression of the a-subunit of the Gq-binding protein, which transduces Ang II signal, and reduced related downstream cellular events such as intracellular Ca 2 þ and IP 3 release and PKC activity. 5,6 This abnormal G-protein-mediated signalling of Ang II shown in BS/GS patients, combined with downregulation of RhoA/Rho-kinase pathway 7 and upregulation of NO system, 5,6 reduced peripheral resistance, vascular hyporeactivity, normo/hypotension typical of these patients and their collection of biochemical characteristics, presents a mirror image of that found in hypertension. In addition, BS/GS patients have unchanged levels of C-reactive protein, serum amyloid A, vascular cell adhesion molecule, intercellular adhesion molecule, interleukin-6 and tumor necrosis factor-a.…”