Hypertensive Cardiac Hypertrophy Research Articles

BMP10 suppresses hepatocellular carcinoma progression via PTPRS-STAT3 axis.

Bone morphogenetic protein 10 (BMP10), one member of the BMP family, is involved in various development events. Dysregulation of BMP10 has been observed in several diseases, including hypertensive cardiac hypertrophy, Hirschsprung disease and blood vessel formation. However, its role in liver cancer remains largely unknown. In this study, we reported that BMP10 was significantly downregulated in HCC at both mRNA and protein level. Decreased BMP10 was associated with bigger tumor size, worse TNM stage, earlier recurrence and poorer survival. BMP10 negatively regulated HCC cell proliferation in vitro and in vivo. Mechanism study revealed that BMP10 suppressed tumor cell growth by inhibiting STAT3 signaling. Interestingly, we found that cytoplasmic BMP10 interacted with both receptor protein tyrosine phosphatase sigma (PTPRS) and STAT3, which facilitated dephosphorylation of STAT3 by PTPRS. Altogether, our study has revealed the clinical significance of BMP10 in HCC, and suppression of HCC cell growth by BMP10 via PTPRS-STAT3 axis, providing a potential therapeutic strategy for targeting STAT3 signaling in HCC.

Inhibition Of Endoplasmic Reticulum Stress As A Potential Therapy To Limit The Progression Of Aaa And Hypertensive Heart Disease

Background and Aims: chronic induction of endoplasmic reticulum (ER) stress and its deleterious relationship with mitochondria are responsible for triggering pathological mechanisms involved in the physiopathology of cardiovascular disease. Therefore, we aim to determine whether inhibition of ER stress is effective to reduce abdominal aortic aneurysm (AAA) development and hypertensive cardiac hypertrophy in an experimental model.

The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via NF-\u03baB dependent downregulation of miRNA-143

Untreated pathological cardiac hypertrophy, which can be caused by sustained systemic hypertension, may lead to heart failure. In the present study, we investigated whether AS-1 had attenuating effects on hypertension-induced cardiac hypertrophy, and whether this process was mediated by the regulation of miRNA-143. To induce the hypertrophic response in vitro, cardiomyocytes were stimulated with Ang II for 24hs. AS-1 administration strongly attenuated Ang II-induced hypertrophic response of cardiomyocytes. Chronical infusion of Ang II via implanted osmotic mini-pump induced increased blood pressure and cardiac hypertrophy in vivo. AS-1 administration attenuated hypertension-induced cardiac hypertrophy by, at least in part, inhibin of MAPK signaling. We observed, for the first time, upregulated expression of miRNA-143 in Ang II-induced cardiomyocytes, and inhibition of miRNA-143 significantly reduced the Ang II-induced hypertrophic responses. Importantly, AS-1 administration diminished the Ang II-induced upregulation of miRNA-143. Overexpression of miRNA-143 abolished the attenuating effects of AS-1 on Ang II-induced hypertrophic response of cardiomyocytes. Additionally, AS-1 administration abrogates Ang II-induced nuclear translocation of p50 NF-κB subunit in hypertrophic cardiomyocytes. Application of NF-κB inhibitor significantly suppressed Ang II-induced upregulation of miRNA-143. Our data suggest a novel mechanism by which AS-1 attenuates Ang II-induced hypertrophic response through downregulation miRNA-143 expression in a NF-κB-dependent manner.

Rutaecarpine prevents hypertensive cardiac hypertrophy involving the inhibition of Nox4‐ROS‐ADAM17 pathway

Rutaecarpine attenuates hypertensive cardiac hypertrophy in the rats with abdominal artery constriction (AAC); however, its mechanism of action remains largely unknown. Our previous study indicated that NADPH oxidase 4 (Nox4) promotes angiotensin II (Ang II)‐induced cardiac hypertrophy through the pathway between reactive oxygen species (ROS) and a disintegrin and metalloproteinase‐17 (ADAM17) in primary cardiomyocytes. This research aimed to determine whether the Nox4‐ROS‐ADAM17 pathway is involved in the protective action of rutaecarpine against hypertensive cardiac hypertrophy. AAC‐induced hypertensive rats were adopted to evaluate the role of rutaecarpine in hypertensive cardiac hypertrophy. Western blotting and real‐time PCR were used to detect gene expression. Rutaecarpine inhibited hypertensive cardiac hypertrophy in AAC‐induced hypertensive rats. These findings were confirmed by the results of in vitro experiments that rutaecarpine significantly inhibited Ang II‐induced cardiac hypertrophy in primary cardiomyocytes. Likewise, rutaecarpine significantly suppressed the Nox4‐ROS‐ADAM17 pathway and over‐activation of extracellular signal‐regulated kinase (ERK) 1/2 pathway in the left ventricle of AAC‐induced hypertensive rats and primary cardiomyocytes stimulated with Ang II. The inhibition of Nox4‐ROS‐ADAM17 pathway and over‐activation of ERK1/2 might be associated with the beneficial role of rutaecarpine in hypertensive cardiac hypertrophy, thus providing additional evidence for preventing hypertensive cardiac hypertrophy with rutaecarpine.

Dynamine-Related Protein 1 (Drp1) Contributes to Hypertensive Cardiac Hypertrophy and Fibrosis In Vivo and In Vitro Model

Dynamine-Related Protein 1 (Drp1) Contributes to Hypertensive Cardiac Hypertrophy and Fibrosis In Vivo and In Vitro Model

UBIAD1 expression is associated with cardiac hypertrophy in spontaneously hypertensive rats.

The present study investigated the potential role of UbiA prenyltransferase domain-containing1 (UBIAD1) in the pathogenesis of hypertensive cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) and Wistar‑Kyoto (WKY) rats at 8, 16 and 28weeks of age were used. Blood pressure was measured using a non‑invasive tail cut‑off system. Cardiac functional index was assessed by arterial catheterization. Myocardial structure and cell apoptosis were evaluated by hematoxylin and eosin staining, and terminal deoxynucleotidyl‑transferase‑mediated dUTP nick end labeling assays, respectively. Myocardial expression of UBIAD1, coenzyme Q10 (CoQ10), endothelial nitric oxide synthase (eNOS) and atrial natriuretic peptide were evaluated by immunohistochemistry, western blotting and reverse transcription‑quantitative polymerase chain reaction. Circulating and myocardial expression of nitric oxide (NO) were measured using the Griess method. SHRs exhibited increased blood pressure and cardiomyocyte apoptosis, as well as cardiac hypertrophy, compared with age‑matched WKY rats. Myocardial expression of UBIAD1 was significantly decreased in SHRs in an age‑dependent manner. Similarly, myocardial CoQ10 and eNOS expression were significantly reduced in SHR compared to age‑matched WKY rats, and these expression levels additionally decreased further with aging. Serum and myocardial NO expression was additionally decreased in SHRs. Decreased UBIAD1 expression in SHR hearts was associated with decreased levels of CoQ10, eNOS and NO. Given the well‑established role of UBIAD1 in the regulation of NO signaling, reduced expression of UBIAD1 in SHR hearts potentially contributed to the pathogenesis of hypertensive cardiac hypertrophy. Therefore, UBIAD1 may represent a potential therapeutic target for clinical treatment of hypertensive cardiac hypertrophy.

Atrial fibrillation in patient with high thrombotic risk: which therapy?

We report the case of an elderly patient suffering for about 20 years of hypertensive cardiac hypertrophy, carotid and peripheral vasculopathy. The patient, initially treated with oral anticoagulant therapy (dicumarol) due to relapsing atrial fibrillation, is an example of long-term use of dabigatran, dictated by safety concern in a patient at high risk of bleeding: as demonstrated by the RE-LY trial, dabigatran 110 mg / day has a preventive effect on cerebral events similar warfarin but with a lower incidence of bleeding. In this case, at high risk both thrombotic and hemorrhagic, the choice of dabigatran was successful in the long term (Cardiology).

PO-148 Effect of Aerobic Exercise on the Expression of CaMKIIδ/MEF2 in Hypertensive and Physiological Cardiac Hypertrophy

Objective The type II calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) signal plays a key role in the development of cardiac hypertrophy. This study used CaMKIIδ as an entry point to investigate the mechanism of moderate-intensity aerobic exercise affecting myocardial function.
 Methods Male spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs), 12 weeks age, were randomly divided into aerobic exercise group (SHR-EX/WKY-EX) and sedentary control group (SHR-SED/WKY-SED), with 12 rats in each group. The aerobic exercise group conducted an 8-week treadmill exercise training with a slope of 0°, 20m/min (about 55-65% of maximal aerobic velocity), 60min/day, and 5d/wk. The control group did not exercise. The body weight of each group of rats was measured weekly and the blood pressure of the rats was measured non-invasively. After 8 weeks, the hearts of SHR-EX group, WKY-EX group, SHR-SED group and WKY-SED group were weighed, and then myocardial tissue sections were taken for HE staining to observe the thickness of the ventricular wall and the morphology of myocardial cells. The expression of CaMKIIδ and MEF2 in each group was determined by Western blotting.
 Results (1) The body weight of SHR-SED group was significantly higher than that of SHR-EX group (p<0.01), and the heart weight of rats in exercise group changed significantly. The WKY-EX group had greater heart weight than the WKY-SED group, and the SHR-SED group was heavier than the SHR-EX group (p<0.05). The heart weight/body weight ratio of the WKY-EX group was significantly higher than that of the WKY-SED group (p<0.01). The heart weight/body weight ratio of SHR-EX group and SHR-SED group was higher than that of WKY-EX group and WKY-SED group (p<0.01). (2) Compared with the WKY-SED group, the SHR-SED group had loose interstitial cells and increased single cell area. The SHR-EX group is more compact than the SHR-SED group, and the cell cross-sectional area is reduced. (3) The expression of CaMKIIδ protein in SHR-EX group was significantly lower than that in SHR-SED group (p<0.01), but the expression level of CaMKIIδ in WKY-EX group was significantly higher than that in WKY-SED group (p<0.01). The expression level of CaMKIIδ was significantly higher in the SHR-SED group than in the WKY-SED group. In addition, the expression of MEF2 protein in SHR-EX group and WKY-SED group was significantly lower than that in SHR-SED group (p<0.01), while the MEF2 expression level in WKY-EX group was higher than WKY-SED group and SHR-EX group (p<0.05).
 Conclusions There is an interaction between aerobic exercise and hypertension. Aerobic exercise can effectively delay the development of hypertensive cardiac hypertrophy by regulating the expression of CaMKIIδ and MEF2 protein in the myocardium, but it can also cause cardiac hypertrophy in normal heart. It is one of the important mechanisms affecting the myocardial morphology and function.
 

GW29-e1456 The TIR/BB-loop mimetic AS-1 prevents Ang II-induced hypertensive cardiac hypertrophy via modulation of miRNA-143

Untreated pathological cardiac hypertrophy, which can be caused by sustained systemic hypertension, may lead to heart failure. The purpose of this study is to determine whether AS-1 had attenuating effects on hypertension-induced cardiac hypertrophy, and whether this process was mediated by the

Mitochondrial fission protein, dynamin-related protein 1, contributes to the promotion of hypertensive cardiac hypertrophy and fibrosis in Dahl-salt sensitive rats

BackgroundHypertension promotes cardiac hypertrophy which finally leads to cardiac dysfunction. Although aberrant mitochondrial dynamics is known to be a relevant contributor of pathogenesis in heart disease, little is known about the relationship between mitochondrial dynamics and cardiac hypertrophy. We investigated the pathophysiological roles of Dynamin-related protein1 (Drp1, a mitochondrial fission protein) on the hypertensive cardiac hypertrophy. Methods & resultsDahl salt-sensitive rats were fed with a low-salt (0.3% NaCl) or a high-salt (8% NaCl) chow to promote hypertension with and without administration of mdivi1 (an inhibitor of Drp1: 1 mg/kg/every alternative day), and then the hypertensive cardiac hypertrophy was assessed. High-salt fed rats exhibited left ventricular hypertrophy (LVH), myocytes hypertrophy, and cardiac fibrosis, and mdivi-1 suppressed them without alteration of the blood pressure. Mdivi1 also reduced ROS production by hypertension, which subsequently suppressed the Ca2+-activated protein phosphatase calcineurin and Ca2+/calmodulin-dependent kinase II (CaMKII). ConclusionsOur results suggest that Drp1 contributes to the pathogenesis of hypertensive cardiac hypertrophy via ROS production and the Drp1 suppression may be effective to prevent the hypertensive cardiac hypertrophy.

Direct Recording of Cardiac and Renal Sympathetic Nerve Activity Shows Differential Control in Renovascular Hypertension.

There is increasing evidence that hypertension is initiated and maintained by elevated sympathetic tone. Increased sympathetic drive to the heart is linked to cardiac hypertrophy in hypertension and worsens prognosis. However, cardiac sympathetic nerve activity (SNA) has not previously been directly recorded in hypertension. We hypothesized that directly recorded cardiac SNA levels would be elevated during hypertension and that baroreflex control of cardiac SNA would be impaired during hypertension. Adult ewes either underwent unilateral renal artery clipping (n=12) or sham surgery (n=15). Two weeks later, electrodes were placed in the contralateral renal and cardiac nerves to record SNA. Baseline levels of SNA and baroreflex control of heart rate and sympathetic drive were examined. Unilateral renal artery clipping induced hypertension (mean arterial pressure 109±2 versus 91±3 mm Hg in shams; P<0.001). The heart rate baroreflex curve was shifted rightward but remained intact. In the hypertensive group, cardiac sympathetic burst incidence (bursts/100 beats) was increased (39±14 versus 25±9 in normotensives; P<0.05), whereas renal sympathetic burst incidence was decreased (69±20 versus 93±8 in normotensives; P<0.01). The renal sympathetic baroreflex curve was shifted rightward and showed increased gain, but there was no change in the cardiac sympathetic baroreflex gain. Renovascular hypertension is associated with differential control of cardiac and renal SNA; baseline cardiac SNA is increased, whereas renal SNA is decreased.

P21-5 - Dynamin-Related Protein1 (Drp1) Contributes to Cardiac Hypertrophy in Salt Sensitive Dahl Rat

Purpose: Hypertension promotes cardiac hypertrophy leading to Heart failure. Although aberrant mitochondrial dynamics is known to contribute to the pathogenesis of heart disease, little is known about the pathophysiological roles of Drp1, a mitochondrial fission protein, on the hypertensive cardiac hypertrophy. Methods and Results: Dahl salt sensitive rats (7 weeks) were started to feed with a chow containing low salt (0.3%: LS-group, n = 8) or high salt (8%: HS-group, n = 8) to induce hypertension. After 9 weeks, HS-group exhibited hypertension (systolic BP: 179.3 ± 8.9 mmHg, P < .01 vs 120.6 ± 4.8 mmHg of LS-group) and cardiac hypertrophy (heart weight/body weight: 0.5 ± 0.02% vs 0.35 ± 0.05%, P < .01). In the histologic analysis, HS-group revealed cardiac hypertrophy (Muscle fiber area: 795 ± 133 µm2, P < .05 vs 305.8 ± 39.5 µm2 of LS-group) and increased fibrosis (fibrotic area in azan staining: 34%, P < .05 vs 20% of LS-group). HS-group showed an increased expression in Drp1, whereas not significant in other mitochondrial dynamics proteins. In HS-group, when mdivi1 (an inhibitor of Drp1) was administered to rats (1 mg/kg by intraperitoneal injection every alternative day), the cardiac hypertrophy was suppressed (heart weight/body weight: 0.4 ± 0.0% with mdivi1, P < .01 vs 0.5 ± 0.02% without mdivi1) without alteration in BP. Conclusion: The myocardial Drp1-expression may be related to the pathogenesis of hypertensive cardiac hypertrophy.

Enhanced endothelin-1/Rho-kinase signalling and coronary microvascular dysfunction in hypertensive myocardial hypertrophy.

Hypertensive cardiac hypertrophy is associated with reduced coronary flow reserve, but its impact on coronary flow regulation and vasomotor function remains incompletely understood and requires further investigation. Left ventricular hypertrophy was induced in mice by transverse aortic coarctation (TAC) for 4 weeks. The left coronary artery blood velocity (LCABV) and myocardium lactate level were measured following the metabolic activation by isoproterenol. Septal coronary arterioles were isolated and pressurized for functional studies. In TAC mice, the heart-to-body weight ratio was increased by 45%, and cardiac fractional shortening and LCABV were decreased by 51 and 14%, respectively. The resting myocardial lactate level was 43% higher in TAC mice. Isoproterenol (5 µg/g, i.p.) increased heart rate by 20% in both groups of animals, but the corresponding increase in LCABV was not observed in TAC mice. The ventricular hypertrophy was associated with elevation of myocardial endothelin-1 (ET-1), increased vascular expression of rho-kinases (ROCKs), and increased superoxide production in the myocardium and vasculature. In coronary arterioles from TAC mice, the endothelial nitric oxide (NO)-mediated dilation to acetylcholine (ACh) was reversed to vasoconstriction and the vasoconstriction to ET-1 was augmented. Inhibition of ROCK by H-1152 alleviated oxidative stress and abolished enhanced vasoconstriction to ET-1. Both H-1152 and superoxide scavenger Tempol abolished coronary arteriolar constriction to ACh in a manner sensitive to NO synthase blocker NG-nitro-L-arginine methyl ester. Myocardial hypertrophy induced by pressure overload leads to cardiac and coronary microvascular dysfunction and ischaemia possibly due to oxidative stress, enhanced vasoconstriction to ET-1 and compromised endothelial NO function via elevated ROCK signalling.

Chrysanthemum morifolium extract improves hypertension-induced cardiac hypertrophy in rats by reduction of blood pressure and inhibition of myocardial hypoxia inducible factor-1alpha expression

Context: Chrysanthemum morifolium Ramat. (Asteraceae) extract (CME) possesses a vasodilator effect in vitro. However, the use of polyphenol-rich CME in the treatment of hypertension-induced cardiac hypertrophy has not been reported.Objective: We investigated the effect of polyphenol-rich CME on hypertension-induced cardiac hypertrophy in rats and its possible mechanism of action.Materials and methods: The Sprague-Dawley rat model with cardiac hypertrophy was induced by renovascular hypertension. The blood pressure, cardiac weight index, free fatty acids (FFA) in serum and myocardium, and protein expressions of myocardial hypoxia inducible factor-1α (HIF-1α), peroxisome proliferator-activated receptor α (PPARα), carnitine palmitoyltransferase-1a (CPT-1a), pyruvate dehydrogenase kinase-4 (PDK-4) and glucose transporter-4 (GLUT-4) were measured after treating hypertensive rats with polyphenol-rich CME of anthodia 75–150 mg/kg once daily for 4 weeks. A myocardial histological examination was also conducted.Results: After CME treatment, the blood pressure, cardiac weight and cardiac weight index decreased by 5.7–9.6%, 9.2–18.4% and 10.9–20.1%, respectively, and the cardiomyocyte cross-sectional area also decreased by 8.3–30.4%. The CME treatment simultaneously decreased the FFA in serum and myocardium and protein expressions of myocardial HIF-1α and GLUT-4, and increased the protein expressions of myocardial PPARα, CPT-1a and PDK-4, especially in the CME 150 mg/kg group (p < 0.05 or p < 0.01).Discussion and conclusion: Polyphenol-rich CME may alleviate hypertensive cardiac hypertrophy in rats. Its mechanisms may be related to the reduction of blood pressure and amelioration of the myocardial energy metabolism. The latter may be attributed to the inhibition of HIF-1α expression and subsequent modulation of PPARα-mediated CPT-1a, PDK-4 and GLUT-4 expressions.

Amlodipine and atorvastatin improved hypertensive cardiac hypertrophy through regulation of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin system in spontaneous hypertension rats

The present study aims to study the role of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) system in cardiac hypertrophy in a spontaneous hypertension rat (SHR) model and the effects of amlodipine and atorvastatin intervention. Thirty-six-week-old male SHRs were randomly divided into four groups: 1) SHR control group; 2) amlodipine alone (10 mg/kg/d) group, 3) atorvastatin alone (10 mg/kg/d) group, 4) combination of amlodinpine and atorvastatin (10 mg/kg/d for each) group. Same gender, weight, and age of Wistar-Kyoto (WKY) rats with normal blood pressure were used as normal control. Drugs were administered by oral gavage over 12 weeks. The thicknesses of left ventricle walls, left ventricle weight, and cardiac function were measured by transthoracic echocardiography. Left ventricular pressure and function were assessed by hemodynamic examination. Cardiomyocyte hypertrophy and collagen accumulation in cardiac tissue were measured by hematoxylin and eosin (HE) and Masson staining, respectively. The hydroxyproline content of cardiac tissue was examined by biochemistry technique. RANKL, RANK and OPG mRNA, protein expression and tissue localization were studied by RT-PCR, Immunohistochemistry and Western blot. Treatment with amlodipine or atorvastatin alone significantly decreased left ventricular mass index, cardiomyocyte cross-sectional area and interstitial fibrosis in SHR (each P < 0.05). Moreover, combined amlodipine and atorvastatin treatment induced significant reversal of left ventricular hypertrophy and decreased cardiomyocyte cross-sectional area and interstitial fibrosis in SHR to a greater extent than each agent alone (P < 0.05). Compared with WKY rats, the myocardial expression of RANKL, RANK, and OPG was increased. Both amlodipine and atorvastatin reduced RANKL, RANK, and OPG expression, with the best effects seen with the combination. Based on our results, activation of the RANKL/RANK/OPG system may be an important factor leading to ventricular remodeling in SHR rats. Amlodipine and atorvastatin could improve ventricular remodeling in SHR rats through intervention with the RANKL/RANK/OPG system.

Apigenin ameliorates hypertension-induced cardiac hypertrophy and down-regulates cardiac hypoxia inducible factor-lα in rats.

Apigenin is a natural flavonoid compound that can inhibit hypoxia-inducible factor (HIF)-1α expression in cultured tumor cells under hypoxic conditions. Hypertension-induced cardiac hypertrophy is always accompanied by abnormal myocardial glucolipid metabolism due to an increase of HIF-1α. However, whether or not apigenin may ameliorate the cardiac hypertrophy and abnormal myocardial glucolipid metabolism remains unknown. This study aimed to examine the effects of apigenin. Rats with cardiac hypertrophy induced by renovascular hypertension were treated with apigenin 50-100 mg kg(-1) (the doses can be achieved by pharmacological or dietary supplementation for an adult person) by gavage for 4 weeks. The results showed that after treatment with apigenin, the blood pressure, heart weight, heart weight index, cardiomyocyte cross-sectional area, serum angiotensin II, and serum and myocardial free fatty acids were reduced. It is important to note that apigenin decreased the expression level of myocardial HIF-1α protein. Moreover, apigenin simultaneously increased the expression levels of myocardial peroxisome proliferator-activated receptor (PPAR) α, carnitine palmitoyltransferase (CPT)-1, and pyruvate dehydrogenase kinase (PDK)-4 proteins and decreased the expression levels of myocardial PPARγ, glycerol-3-phosphate acyltransferase genes (GPAT), and glucose transporter (GLUT)-4 proteins. These findings demonstrated that apigenin could improve hypertensive cardiac hypertrophy and abnormal myocardial glucolipid metabolism in rats, and its mechanisms might be associated with the down-regulation of myocardial HIF-1α expression and, subsequently increasing the expressions of myocardial PPARα and its target genes CPT-1 and PDK-4, and decreasing the expressions of myocardial PPARγ and its target genes GPAT and GLUT-4.

Abstract 13955: Small Conductance Ca2+-activated K+ Current is Upregulated via the Phospholylation of CaMKII in Cardiac Hypertrophy

Background: Left ventricular hypertrophy is associated with increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca2+-activated K+ (SK) channel is involved in the pathogenesis of ventricular arrhythmias in heart failure. We have recently reported that the activity of calcium/calmodulin-dependent protein kinase II (CaMKII) is increased in hypertensive cardiac hypertrophy. Objective: The aim of this study is to test the hypothesis that SK channels activity is increased via the CaMKII-dependent pathway in hypertensive cardiac hypertrophy. Methods and Results: We used normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Whole cell membrane current was recorded in isolated ventricular myocyte by the patch-clamp method, and apamin-sensitive K+ current (IKAS), inhibited by apamin (100 nM), a blocker of SK channel, was evaluated. IKAS at 40 mV was present in SHR, whereas it was hardly detectable in WKY (0.579±0.046 pA/pF vs 0.022±0.062 pA/pF, both n=6, p&lt;0.05). IKAS was almost completely abolished by 1 μM KN-93, an inhibitor of CaMKII, in SHR. Optical recordings of action potential in left ventricular anterior wall revealed that apamin prolonged the late phase of repolarization only in SHR (APD90 113.07±3.62 vs 124.95±3.62 msec, both n=4, p&lt;0.05, and APD50 37.53±4.21 vs 50.48±4.21 msec, both n=4, p&lt;0.05). Western blot analysis of SK channel protein isoform demonstrated that SK2 was significantly increased in SHR compared to WKY (SK2/GAPDH 0.66±0.07 vs 0.40±0.02, both n=6, p&lt;0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHR (pCaMKII/GAPDH 0.80±0.06 vs 0.58±0.06, both n=6, p&lt;0.05) despite comparable total amount of CaMKII between groups. Conclusion: SK channels are upregulated via the enhanced activation of CaMKII in hypertensive cardiac hypertrophy.

Small-conductance Ca2+-activated K+ current is upregulated via the phosphorylation of CaMKII in cardiac hypertrophy from spontaneously hypertensive rats.

Left ventricular hypertrophy is associated with an increased risk of ventricular arrhythmias. However, the underlying molecular basis is poorly understood. It has been reported that small-conductance Ca(2+)-activated K(+) (SK) channels are involved in the pathogenesis of ventricular arrhythmias in heart failure. The present study aimed to test the hypothesis that SK channel activity is increased via the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway in hypertensive cardiac hypertrophy. Normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) were used. Whole cell membrane currents were recorded in isolated ventricular myocytes by the patch-clamp method, and apamin-sensitive K(+) current (IKAS), which is inhibited by apamin (100 nM), an SK channel blocker, was evaluated. IKAS at 40 mV was present in SHRs, whereas it was hardly detectable in WKY rats (0.579 ± 0.046 vs. 0.022 ± 0.062 pA/pF, both n = 6, P < 0.05). IKAS was almost completely abolished by 1 μM KN-93, a CaMKII inhibitor, in SHRs. Optical recordings of left ventricular anterior wall action potentials revealed that apamin prolonged the late phase of repolarization only in SHRs. Western blot analysis of SK channel protein isoforms demonstrated that SK2 was significantly increased in SHRs compared with WKY rats (SK2/GAPDH: 0.66 ± 0.07 vs. 0.40 ± 0.02, both n = 6, P < 0.05), whereas SK1 and SK3 did not differ between groups. In addition, autophosphorylated CaMKII was significantly increased in SHRs (phosphorylated CaMKII/GAPDH: 0.80 ± 0.06 vs. 0.58 ± 0.06, both n = 6, P < 0.05) despite a comparable total amount of CaMKII between groups. In conclusion, SK channels are upregulated via the enhanced activation of CaMKII in cardiac hypertrophy in SHRs.

The Nuclear Factor kappaB Inhibitor Pyrrolidine Dithiocarbamate Prevents Cardiac Remodelling and Matrix Metalloproteinase-2 Up-Regulation in Renovascular Hypertension.

Imbalanced matrix metalloproteinase (MMP) activity is involved in hypertensive cardiac hypertrophy. Pharmacological inhibition of nuclear factor kappaB (NF-кB) with pyrrolidine dithiocarbamate (PDTC) can prevent MMP up-regulation. We suggested that treatment with PDTC could prevent 2-kidney, 1-clip (2K1C) hypertension-induced left ventricular remodelling. Sham-operated controls or 2K1C rats with hypertension received either vehicle or PDTC (100mg/kg/day) by gavage for 8weeks. Systolic blood pressure was monitored every week. Histological assessment of left ventricles was carried out with haematoxylin/eosin sections, and fibrosis was quantified in picrosirius red-stained sections. Oxidative stress was evaluated in heart samples with the dihydroethidium probe. Cardiac MMP activity was determined by in situ zymography, and cardiac MMP-2 was assessed by immunofluorescence. 2K1C surgery significantly increased systolic blood pressure in the 2K1Cvehicle. PDTC exerted antihypertensive effects after 2weeks of treatment. Histology revealed increased left ventricular and septum wall thickness associated with augmented myocyte diameter in hypertensive rats, which were reversed by treatment with PDTC. Hypertensive rats developed pronounced cardiac fibrosis with increased interstitial collagen area, increased cardiac reactive oxygen species levels, gelatinase activity and MMP-2 expression. PDTC treatment decreased these alterations. These findings show that PDTC modulates myocardial MMP-2 expression and ameliorates cardiac remodelling in renovascular hypertension. These results suggest that interfering with MMP expression at transcriptional level may be an interesting strategy in the therapy of organ damage associated with hypertension.

The immune system and hypertension.

A powerful interaction between the autonomic and the immune systems plays a prominent role in the initiation and maintenance of hypertension and significantly contributes to cardiovascular pathology, end-organ damage and mortality. Studies have shown consistent association between hypertension, proinflammatory cytokines and the cells of the innate and adaptive immune systems. The sympathetic nervous system, a major determinant of hypertension, innervates the bone marrow, spleen and peripheral lymphatic system and is proinflammatory, whereas the parasympathetic nerve activity dampens the inflammatory response through α7-nicotinic acetylcholine receptors. The neuro-immune synapse is bidirectional as cytokines may enhance the sympathetic activity through their central nervous system action that in turn increases the mobilization, migration and infiltration of immune cells in the end organs. Kidneys may be infiltrated by immune cells and mesangial cells that may originate in the bone marrow and release inflammatory cytokines that cause renal damage. Hypertension is also accompanied by infiltration of the adventitia and perivascular adipose tissue by inflammatory immune cells including macrophages. Increased cytokine production induces myogenic and structural changes in the resistance vessels, causing elevated blood pressure. Cardiac hypertrophy in hypertension may result from the mechanical afterload and the inflammatory response to resident or migratory immune cells. Toll-like receptors on innate immune cells function as sterile injury detectors and initiate the inflammatory pathway. Finally, abnormalities of innate immune cells and the molecular determinants of their activation that include toll-like receptor, adrenergic, cholinergic and AT1 receptors can define the severity of inflammation in hypertension. These receptors are putative therapeutic targets.