Role of Kinins in Hypertension and Heart Failure

Abstract

The kallikrein–kinin system (KKS) is proposed to act as a counter regulatory system against the vasopressor hormonal systems such as the renin-angiotensin system (RAS), aldosterone, and catecholamines. Evidence exists that supports the idea that the KKS is not only critical to blood pressure but may also oppose target organ damage. Kinins are generated from kininogens by tissue and plasma kallikreins. The putative role of kinins in the pathogenesis of hypertension is discussed based on human mutation cases on the KKS or rats with spontaneous mutation in the kininogen gene sequence and mouse models in which the gene expressing only one of the components of the KKS has been deleted or over-expressed. Some of the effects of kinins are mediated via activation of the B2 and/or B1 receptor and downstream signaling such as eicosanoids, nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF) and/or tissue plasminogen activator (T-PA). The role of kinins in blood pressure regulation at normal or under hypertension conditions remains debatable due to contradictory reports from various laboratories. Nevertheless, published reports are consistent on the protective and mediating roles of kinins against ischemia and cardiac preconditioning; reports also demonstrate the roles of kinins in the cardiovascular protective effects of the angiotensin-converting enzyme (ACE) and angiotensin type 1 receptor blockers (ARBs).

A Differential Pattern of Batokine Expression in Perivascular Adipose Tissue Depots From Mice

“…We know far less about human PVAT compared to that in rodent models and there are indications that human PVAT has somewhat distinct features relative to mice. In spite of that, recent studies reported that human tPVAT shows some BAT/beige features (for instance Ucp1 expression; Wei et al, 2015 ; Vargas et al, 2018 ; Hamid et al, 2020 ), whereas aPVAT resembles WAT. The plasticity of human PVAT depots in response to thermogenic stimuli is unknown, but a recent study based on autopsies of Siberian adults indicated that almost one half the individuals assessed exhibited multilocular adipocytes, paucilocular adipocytes, and UCP1 expression in mediastinal peri-aortic PVAT ( Efremova et al, 2020 ).…”

“…2015; Vargas et al, 2018;Hamid et al, 2020), whereas aPVAT resembles WAT. The plasticity of human PVAT depots in response to thermogenic stimuli is unknown, but a recent study based on autopsies of Siberian adults indicated that almost one half the individuals assessed exhibited multilocular adipocytes, paucilocular adipocytes, and UCP1 expression in mediastinal peri-aortic PVAT (Efremova et al, 2020).…”

“…Thus, we can expect that local secretion of BMP8B by brown/beige-activated PVAT could exert analogous effects on attached large vessels. Published findings suggest that kininogens, which are key components of the kinin-kallikrein system, play a role in the cardiovascular system, such as preventing hypertension and ischemia ( Hamid et al, 2020 ). Gdf15 and Vegfa appear to be particularly induced in tPVAT in response to cold.…”

“…Some batokines, such as kininogen-2 (KNG2) and possibly fibroblast growth factor-21 (FGF21), have been shown to influence the vascular system in experimental settings unrelated to a brown/beige adipose origin ( Domouzoglou et al, 2015 ; Hamid et al, 2020 ). Vascular endothelial growth factor-A (VEGFA) and bone morphogenetic protein-8b (BMP8B) secreted specifically from brown adipocytes were shown to promote vascularization at BAT depots ( Tonello et al, 1999 ; Xue et al, 2009 ; Pellegrinelli et al, 2018 ).…”

Role of Matricellular CCN Proteins in Skeletal Muscle: Focus on CCN2/CTGF and Its Regulation by Vasoactive Peptides

“…In the same diabetes model, the overexpression of human kallikrein promoted neovascularization, suppressed apoptosis, and upregulated endothelial nitric oxide synthase expression, protecting hindlimb from ischemic damage [ 167 ]. Another mechanism for hypoxia could be the impairment of the vascular vasodilatory response since in endothelial cells BK leads to a potent vasodilation response that can be mediated by nitric oxide (NO) through the activation of endothelial NO synthase (eNOS), prostacyclin (PGI 2 ), and endothelial hyperpolarizing factor (EDHF) [ 168 , 169 ]. Interestingly, in the dog model of DMD, vascular endothelial dysfunction was reduced by bradykinin infusion, restoring the response to acetylcholine in the vascular bed, and effect that was dependent on NO, through the upregulation of eNOS and nNOS.…”