Person:

Khalil, Raouf

Blood pressure (BP) is regulated by multiple neuronal, hormonal, renal and vascular control mechanisms. Changes in signaling mechanisms in the endothelium, vascular smooth muscle (VSM) and extracellular matrix cause alterations in vascular tone and blood vessel remodeling and may lead to persistent increases in vascular resistance and hypertension (HTN). In VSM, activation of surface receptors by vasoconstrictor stimuli causes an increase in intracellular free Ca2+ concentration ([Ca2+]i), which forms a complex with calmodulin, activates myosin light chain (MLC) kinase and leads to MLC phosphorylation, actin-myosin interaction and VSM contraction. Vasoconstrictor agonists could also increase the production of diacylglycerol which activates protein kinase C (PKC). PKC is a family of Ca2+-dependent and Ca2+-independent isozymes that have different distributions in various blood vessels, and undergo translocation from the cytosol to the plasma membrane, cytoskeleton or the nucleus during cell activation. In VSM, PKC translocation to the cell surface may trigger a cascade of biochemical events leading to activation of mitogen-activated protein kinase (MAPK) and MAPK kinase (MEK), a pathway that ultimately increases the myofilament force sensitivity to [Ca2+]i, and enhances actin-myosin interaction and VSM contraction. PKC translocation to the nucleus may induce transactivation of various genes and promote VSM growth and proliferation. PKC could also affect endothelium-derived relaxing and contracting factors as well as matrix metalloproteinases (MMPs) in the extracellular matrix further affecting vascular reactivity and remodeling. In addition to vasoactive factors, reactive oxygen species, inflammatory cytokines and other metabolic factors could affect PKC activity. Increased PKC expression and activity have been observed in vascular disease and in certain forms of experimental and human HTN. Targeting of vascular PKC using PKC inhibitors may function in concert with antioxidants, MMP inhibitors and cytokine antagonists to reduce VSM hyperactivity in certain forms of HTN that do not respond to Ca2+ channel blockers.

Several studies suggest that infrarenal aortic diameter is associated with lower-extremity peripheral artery disease (LE-PAD). However, data regarding the associations between infrarenal aortic diameter and LE-PAD are limited, especially in large sample populations and Asian or Chinese populations. Our analysis included 17279 Chinese hypertensive adults comprising 6590 men and 10689 women with a mean age of 64.74 ± 7.41 years. Participants were selected from 22693 candidates from two large population-based cohort-studies. The primary noninvasive test for diagnosis of LE-PAD is the ankle–brachial index (ABI) at rest and typically an ABI ≤ 0.90 is used to define LE-PAD. The prevalence of LE-PAD was found to significantly decrease as the aortic diameter increased according to the tertile of the aortic diameter. LE-PAD was significantly more prevalent in the lowest tertile (OR = 1.58, 95% CI = 1.29–1.94, p < 0.001) and similarly prevalent in the highest tertile (OR = 0.92, 95% CI = 0.73–1.16, p = 0.49) when compared with the median tertile. No significant interactions between the aortic diameter and any of the stratified variables were found (all p > 0.05). In conclusion, Small aortic diameter (as opposed to large aortic diameter) is significantly associated with LE-PAD in Chinese hypertensive adults.

Objective: The aim of this study was to investigate the effect and mechanism by which progesterone regulates uterine contraction in late pregnant rats Results: Progesterone caused concentration-dependent relaxation of uterine strips that was enhanced compared with control nontreated uterine strips. Uterine strips incubated with progesterone showed a significant increase in TREK-1 mRNA expression and protein level. TREK-1 inhibitor L-methionine partly reversed uterine relaxation caused by the progesterone, while TREK-1 activator arachidonic acid did not cause significant change in progesterone-induced relaxation. Conclusions: Progesterone inhibits uterine contraction and induces uterine relaxation in late pregnancy. The progesterone-induced inhibition of uterine contraction appears to partly involve increased potassium channel TREK-1 expression/activity. Materials and Methods Uterus from late-pregnant rats (gestational day 19) was isolated, and uterine strips were prepared for isometric contraction measurement. Oxytocin-induced contraction was compared in uterine strips pretreated with different concentration of progesterone. TREK-1 potassium channel inhibitor L-methionine and TREK-1 agonist arachidonic acid were used to determine whether the changes caused by progesterone involve changes in TREK-1 activity. The mRNA and protein expression of TREK-1 in uterine tissues were measured using qPCR and Western blot.