Death-Associated Protein Kinase 3 Mediates Vascular Inflammation and Development of Hypertension in Spontaneously Hypertensive Rats

Abstract

C almodulin (CaM) is recognized as a key regulatory molecule for diverse biological functions, such as muscular contraction.1 In addition, a recent study demonstrated that CaM-dependent protein kinases, such as CaM-dependent protein kinase II, may regulate hypertension through the mechanisms including promotion of vascular smooth muscle hypertrophy. 2 In the previous study, we compared expression levels of several CaM-related proteins with almost unknown functions in vasculature. As a result, we demonstrated that protein expression of eukaryotic elongation factor 2 kinase (also known as CaM-dependent protein kinase III), histone deacetylase 4, and death associated protein kinase (DAPK) 3 increased in the mesenteric artery from spontaneously hypertensive rats (SHRs) compared with Wistar Kyoto rats (WKYs). 3 In the recent study, we also showed that histone deacetylase 4 promotes reactive oxygen species (ROS)-dependent vascular inflammation and mediates the development of hypertension in SHRs. 4 However, it remains to be clarified how DAPK3, might affect vascular patholophysiology and control the development of hypertension. The DAPK protein has been considered as a Ca 2+ /CaMregulated serine/threonine kinase that mainly mediates cell death. 5 The DAPK protein consists of multiple domains, including an N-terminal kinase domain (known as a Ca 2+ /CaM regulatory region), ankyrin repeats, a cytoskeleton binding region, and a C-terminal death domain.6 Various stimulation-induced intracellular calcium spikes promote the CaM binding to the CaM regulatory region of DAPK, which in turn activates DAPK.7 Five protein kinases, including DAPK1, DAPK2, DAPK3 (also known as Zipper-interacting protein kinase), DAPK-related apoptosis-inducing protein kinase 1, and DAPK-related apoptosis-inducing protein kinase 2, are known as DAPK family proteins.8 DAPK1, DAPK2, and DAPK3 are all ubiquitously expressed in various tissues from mice and rats.6 Recently, the functions of DAPK3 were gradually clarified. The mutation of DAPK3 Abstract-Death-associated protein kinase (DAPK) is a Ca 2+ /calmodulin-regulated serine/threonine kinase that mediates cell death. Our recent study demonstrated that DAPK3 protein increases in the mesenteric artery from spontaneously hypertensive rats compared with Wistar Kyoto rats. Pathogenesis of hypertension is modulated at least in part by vascular inflammation. We examined whether DAPK3 mediates vascular inflammatory responses and development of hypertension. In rat mesenteric arterial smooth muscle cells, small interfering RNA against DAPK3 inhibited vascular cell adhesion molecule 1 expression and monocyte adhesion induced by tumor necrosis factor-α. DAPK3 small interfering RNA inhibited phosphorylation of c-Jun amino-terminal kinase, p38, and Akt, as well as reactive oxygen species (ROS) production induced by tumor necrosis factor-α. In human umbilical vein endothelial cells, expressions of vascular cell adhesion molecule 1, endothelial selectin, and cyclooxygenase 2, as well as ROS production induced ...

A Novel Adipocytokine, Omentin, Inhibits Agonists-Induced Increases of Blood Pressure in Rats

“…Because previous reports demonstrated that NO-mediated endothelium-dependent relaxation was impaired in the artery from SHR [6,11,12], this observation may support the idea that the effect of omentin was endothelial NOdependent. However, since our previous results suggested the NO-independent component of vasodilation by omentin in isolated blood vessel [15], we cannot completely exclude the possibility that omentin may reduce the agonists-induced increases in BP via NO-independent mechanisms.…”

“…Body weight, heart rate (HR), systolic blood pressure (BP) (SBP), mean BP (MBP) and diastolic BP (DBP) represent the average value (Table 1). Noninvasive BP in conscious rats was measured using a tail-cuff method after heating the rats (38°C) (Softron, Tokyo, Japan) [6,11,12]. L-NAME was dissolved in drinking water and given to rats (80 mg/kg, 1 day).…”

Mitochondrial Fission of Smooth Muscle Cells Is Involved in Artery Constriction

“…15 We wondered whether the responses of mesenteric arteries to phenylephrine and KPSS stimuli were different between SHRs and Wistar Kyoto (WKY) rats after mitochondrial fission inhibition. SHRs showed increased systolic blood pressure, diastolic blood pressure, and heart body ratio ( Figure S10A and S10B).…”

Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats

“…27 SHR exhibited more profound inflammatory status in mesenteric arteries. 28 NF-kB and VCAM-1 both actively participate in vascular inflammation. 29 The increased expression of VCAM-1 is a marker of vascular inflammation, vascular permeability, and endothelial dysfunction, [30][31][32] and the NF-kB is a well-studied regulator for inflammation.…”