Abdominal Aortic Banding Research Articles

Upregulation of prolactin receptor in proximal tubular cells was induced in cardiac dysfunction model mice

In order to clarify the interaction between cardiac dysfunction and sodium homeostasis in the kidney, we used a murine model of cardiac dysfunction and investigated the effect on sodium transporters in renal tubular cells. Cardiac function was deteriorated by abdominal aortic banding, and the gene expression of sodium transporters in the kidneys was evaluated by real-time RT-PCR and compared with that in the kidneys of control mice. Gene expression of all three variants of the murine prolactin receptor was enhanced by aortic banding. Upregulated prolactin receptor was distributed in the proximal tubular cells of the pars recta in the deep inner cortex and the outer stripe of the outer medulla. Prolactin has been reported to be a natriuretic hormone that inhibits proximal tubular Na(+)/K(+)-ATPase activity, resulting in reduced sodium reabsorption and the acceleration of natriuresis. Inhibition of endogenous prolactin secretion by bromocriptine administration decreased the urine sodium excretion in both aortic banding and control mice. On the other hand, excess exogenous prolactin administration enhanced urine potassium excretion in aortic banding mice. Furthermore, a high-sodium diet accelerated urinary sodium excretion, which was also significantly decreased by inhibition of endogenous prolactin secretion in aortic banding mice. We reported that the prolactin receptor was upregulated by aortic banding treatment. Prolactin-prolactin receptor interaction in the proximal tubular cells of the pars recta should involve a different mechanism of kaliuresis other than inhibition of Na(+)/K(+)-ATPase.

Modulation of haemodynamics, endogeneous antioxidant enzymes, and pathophysiological changes by selective inhibition of angiotensin II type 1 receptors in pressure-overload rats : cardiovascular topics

Constriction of the thoracic or abdominal aorta provides an experimental model of pressure-overload cardiac hypertrophy. Blockade of AT1 receptors is beneficial in preventing target-organ damage in hypertension. To examine the effect of angiotensin II receptor antagonists on blood pressure, endogenous antioxidant enzyme and histopathological changes in pressure-overload rats. Pressure overload was produced by abdominal aortic banding (AAB) using a blunt 22-guage needle in male rats as a model of cardiac hypertrophy. After surgery, the AAB-induced hypertension (AABIH) rats were treated with losartan 40 mg/kg/day, candesartan 10 mg/kg/day, irbesartan 10 mg/kg/day per os for 16 weeks. At 16 weeks of surgery, the rats were observed for general characteristics and mortality, and we determined non-invasive blood pressure (NIBP), endogenous antioxidant enzyme catalase and superoxide dismutase (SOD) activities, and histology of the target organs. In the AABIH group, significant increase in systolic blood pressure was observed from weeks 3 to 16 compared with the control group, along with reduced serum catalase and SOD activities. The treated groups showed significant reduction in systolic BP and increase in serum SOD and catalase activities. The histological changes induced in the target organs, namely heart, liver, kidneys and thoracic aorta in the AABIH rats were attenuated in the treated rats. Blockade of the AT1 receptor caused an improvement in the myocardial antioxidant reserve and decreased oxidative stress in the hypertensive rats, which was evidenced by the protection observed in the treatment groups.

Expression of lipogenic genes is upregulated in the heart with exercise training-induced but not pressure overload-induced left ventricular hypertrophy

Cardiac hypertrophy is accompanied by molecular remodeling that affects different cellular pathways, including fatty acid (FA) utilization. In the present study, we show that cardiac lipid metabolism is differentially regulated in response to physiological (endurance training) and pathological [abdominal aortic banding (AAB)] hypertrophic stimuli. Physiological hypertrophy was accompanied by an increased expression of lipogenic genes and the activation of sterol regulatory element-binding protein-1c and Akt signaling. Additionally, FA oxidation pathways regulated by AMP-activated protein kinase (AMPK) and peroxisome proliferator activated receptor-α (PPARα) were induced in trained hearts. Cardiac lipid content was not changed by physiological stimulation, underlining balanced lipid utilization in the trained heart. Moreover, pathological hypertrophy induced the AMPK-regulated oxidative pathway, whereas PPARα and expression of its downstream targets, i.e., acyl-CoA oxidase and carnitine palmitoyltransferase I, were not affected by AAB. In contrast, pathological hypertrophy leads to cardiac triglyceride (TG) and diacylglycerol (DAG) accumulation, although the expression of lipogenic genes and the levels of FA transport proteins (CD36 and FATP) were not changed or reduced compared with the sham group. A possible explanation for this phenomenon is a decrease in lipolysis, as evidenced by the increased content of adipose triglyceride lipase inhibitor G0S2, the increased phosphorylation of hormone-sensitive lipase at Ser(565), and the decreased protein levels of DAG lipase that attenuate TG and DAG contents. The increased TG and DAG accumulation observed in AAB-induced hypertrophy might have lipotoxic effects, thereby predisposing to cardiomyopathy and heart failure in the future.

Overexpression of lipogenic genes in the heart distinguishes physiologic from pathologic left ventricle hypertrophy

Molecular remodeling in the heart caused by hypertrophy differs between physiological and pathological stimuli. The main goal of this study was to determine how cardiac hypertrophy that is induced by pressure overload or endurance training influences lipid metabolism in the myocardium. The expression of lipogenic genes was upregulated in exercise‐induced hypertrophy and was accompanied by the activation of fatty acid (FA) oxidation pathways regulated by AMPK and RRARα. Intracellular diacylglyceride (DAG), triglyceride (TG) and free FA were not changed in trained compared with untrained hearts. In contrast, in the heart with abdominal aortic banding (AAB)‐induced hypertrophy, we found an increased accumulation of TG and DAG, although the expression of lipogenic genes and the level of FA transport proteins were not augmented. Cardiac steatosis in AAB‐induced hypertrophy was associated with decreased lipolysis, as evidenced by increased hormone‐sensitive lipase phosphorylation at Ser565 and decreased DAG lipase‐α and ‐β protein levels. Obtained results show that cardiac lipid metabolism is differentially regulated in response to physiological and pathological hypertrophic stimuli and suggest that activation of lipogenesis might be involved in the regulatory mechanisms of heart adaptation to stress. Support: NCN UMO‐2011/01/D/NZ3/04777, NCBR LIDER/19/2/L‐2/10/NCBiR/2011.

CCN2/CTGF attenuates myocardial hypertrophy and cardiac dysfunction upon chronic pressure-overload

Myocardial CCN2/CTGF (connective tissue growth factor) is strongly induced in heart failure (HF) and acts as a cardioprotective factor in ischemia/reperfusion injury. However, its functional role in myocardial hypertrophy remains unresolved. Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate control (NLC) mice were subjected to chronic pressure-overload by abdominal aortic banding. After 4weeks of persistent pressure-overload, a time point at which compensatory hypertrophy of the left ventricle (LV) prevails, Tg-CTGF mice displayed diminished increase of LV mass compared with NLC. At study end-point after 12 weeks of sustained aortic constriction, the mice displayed LV dilatation and reduced cardiac function. Repeated transthoracic echocardiography during the 12 weeks of chronic pressure-overload, revealed attenuation of LV dilatation and virtually sustained systolic function in Tg-CTGF mice compared with NLC mice. Also, increase of LV mass was blunted in Tg-CTGF versus NLC mice at study end-point. Consistently, increases of myocardial ANP, BNP and skeletal α-actin mRNA levels were blunted in Tg-CTGF mice subjected to chronic pressure-overload. Furthermore, cardiac myocytes from Tg-CTGF mice displayed increased phospho-NFATc2 levels and attenuated hypertrophic response upon stimulation with α1-adrenoceptor agonist, indicating that CTGF attenuates hypertrophic signaling in cardiac myocytes. Increase of myocardial collagen contents in mice subjected to aortic banding was similar in Tg-CTGF and NLC mice, indicating that CTGF have minimal impact on myocardial collagen deposition. This study provides novel evidence that CTGF attenuates cardiac hypertrophy upon chronic pressure-overload due to inhibition of signaling mechanisms that promote pathologic myocardial hypertrophy.

Decreased cardiac mitochondrial tetrahydrobiopterin in a rat model of pressure overload

Sustained cardiac pressure overload induces mitochondrial dysfunction and apoptosis of cardiomyocytes leading to pathological cardiac hypertrophy and dysfunction. Mitochondrial nitric oxide synthase (NOS) appears to cause uncoupling, which produces reactive oxygen species (ROS) instead of nitric oxide (NO), by a decrease in the cofactor tetrahydrobiopterin (BH4). This study focused on examining the changes in mitochondrial BH4 levels during cardiac pressure overload. Chronic cardiac pressure overload was generated by abdominal aortic banding in rats. Levels of BH4 and its oxidized form were measured in the mitochondria isolated from the left ventricle (LV) and the post-mitochondrial supernatants. Chronic aortic banding increased blood pressure, and induced cardiac hypertrophy and fibrosis. Notably, the BH4 levels were decreased while its oxidized forms were increased in LV mitochondria, but not in the post-mitochondrial supernatants containing the cytosol and microsome. Anti-neuronal NOS antibody-sensitive protein was detected in the cardiac mitochondria. Moreover, continuous administration of BH4 to rats with pressure overload increased mitochondrial BH4 levels and reduced cardiac fibrosis and matrix metallopeptidase activity, but not cardiac hypertrophy. These findings show the possibility that NOS uncoupling by decreased cardiac mitochondrial BH4 levels is implicated, at least in part, in the development of cardiac fibrosis, leading to cardiac dysfunction induced by pressure overload.

Vascular Endothelial σ<sub>1</sub>-Receptor Stimulation With SA4503 Rescues Aortic Relaxation via Akt/eNOS Signaling in Ovariectomized Rats With Aortic Banding

We previously reported that σ1-receptor (σ1R) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ1R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. SA4503 (0.3-1.0mg/kg) and NE-100 (a σ1R antagonist, 1.0mg/kg) were administered orally for 4 weeks (once daily) to OVX-PO rats. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. SA4503 administration rescued PO-induced σ1R decreases in aortic smooth muscle and endothelial cells. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. The SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. σ1R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ1R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ1R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ1R to prevent vascular endothelial injury in vascular diseases.

Cardiomyocyte-restricted inhibition of G protein-coupled receptor kinase-3 attenuates cardiac dysfunction after chronic pressure overload

Transgenic mice with cardiac-specific expression of a peptide inhibitor of G protein-coupled receptor kinase (GRK)3 [transgenic COOH-terminal GRK3 (GRK3ct) mice] display myocardial hypercontractility without hypertrophy and enhanced α(1)-adrenergic receptor signaling. A role for GRK3 in the pathogenesis of heart failure (HF) has not been investigated, but inhibition of its isozyme, GRK2, has been beneficial in several HF models. Here, we tested whether inhibition of GRK3 modulated evolving cardiac hypertrophy and dysfunction after pressure overload. Weight-matched male GRK3ct transgenic and nontransgenic littermate control (NLC) mice subjected to chronic pressure overload by abdominal aortic banding (AB) were compared with sham-operated (SH) mice. At 6 wk after AB, a significant increase of cardiac mass consistent with induction of hypertrophy was found, but no differences between GRK3ct-AB and NLC-AB mice were discerned. Simultaneous left ventricular (LV) pressure-volume analysis of electrically paced, ex vivo perfused working hearts revealed substantially reduced systolic and diastolic function in NLC-AB mice (n = 7), which was completely preserved in GRK3ct-AB mice (n = 7). An additional cohort was subjected to in vivo cardiac catheterization and LV pressure-volume analysis at 12 wk after AB. NLC-AB mice (n = 11) displayed elevated end-diastolic pressure (8.5 ± 3.1 vs. 2.9 ± 1.2 mmHg, P < 0.05), reduced cardiac output (3,448 ± 323 vs. 4,488 ± 342 μl/min, P < 0.05), and reduced dP/dt(max) and dP/dt(min) (both P < 0.05) compared with GRK3ct-AB mice (n = 16), corroborating the preserved cardiac structure and function observed in GRK3ct-AB hearts assessed ex vivo. Increased cardiac mass and myocardial mRNA expression of β-myosin heavy chain confirmed the similar induction of cardiac hypertrophy in both AB groups, but only NLC-AB hearts displayed significantly elevated mRNA levels of brain natriuretic peptide and myocardial collagen contents as well as reduced β(1)-adrenergic receptor responsiveness to isoproterenol, indicating increased LV wall stress and the transition to HF. Inhibition of cardiac GRK3 in mice does not alter the hypertrophic response but attenuates cardiac dysfunction and HF after chronic pressure overload.

KS370G, a synthetic caffeamide derivative, improves left ventricular hypertrophy and function in pressure-overload mice heart

Cardiac hypertrophy is an important compensatory mechanism in response to a pressure overload, but a sustained excessive cardiac workload may deteriorate to maladaptive hypertrophy and to increased risk of heart failure. In this study, we evaluated the effects of KS370G on left ventricular hypertrophy and function. Abdominal aortic banding was performed by constricting the abdominal aorta. Hypertrophied heart was studied at 8weeks after the operation. After the operation, KS370G 1mg/kg (K1 group) was administered by oral gavage once a day. Left ventricular function was measured by a 1.2F pressure-volume catheter (Scisense, Canada). The levels of protein for α-SMA (smooth muscle actin), p-AKT (protein kinase B), p-GSK3β (glycogen synthase kinase 3β) and p-ERKs (extracellular signal-regulated kinases) in myocardium were analyzed by Western blot. Plasma levels of angiotensin II, atrial natriuretic peptide and lactate dehydrogenase were analyzed by commercial kits. H.E. staining and M.T. staining methods were also used to observe diameter of cardiomyocytes and collagen accumulation. Chronic oral treatment with 1mg/kg KS370G inhibited cardiac hypertrophy and improved cardiac function induced by pressure overload. KS370G also decreased the plasma levels of atrial natriuretic peptide and lactate dehydrogenase. Besides, pressure overload-induced increase of α-SMA and phosphorylation of ERK, AKT and GSK3β were significantly reduced by chronic oral treatment with KS370G. We also found that chronic oral treatment with KS370G reduced cardiac collagen accumulation. KS370G improved left ventricular function and inhibited cardiac hypertrophy through the decrease of the phosphorylation of ERK, AKT and GSK3β in pressure-overload mice heart.

5-HT3 receptor antagonists protect against pressure overload-induced cardiac hypertrophy in murine

Activation of cardiac sympathetic afferent reflex results in the increase of sympathetic activity. Serotonin (5-HT) activates cardiac sympathetic afferent through stimulating 5-HT3 receptors, the aim of present study is to test whether 5-HT3 receptor antagonists protect against cardiac hypertrophy. Cardiac hypertrophy induced by TAC for 4 weeks in mice was significantly inhibited by administration of 5-HT3 receptor antagonists, ondansetron (2.5mg/kg, ip.) or tropisetron (2.5mg/kg, ip.). Histological analysis revealed that the increased cardiac fibrosis in hypertrophic heart was relieved by ondansetron or tropisetron treatment. Ondansetron or tropisetron reduced the elevated plasma level of noradrenalin in mice with cardiac hypertrophy. Ondansetron and tropisetron had no effect on cardiomyocte hypertrophy induced by phenylephrine treatment in vitro. Finally, we took tropisetron as the representative drug and examined the effects of tropisetron on the desensitization of cardiac β-adrenergic receptor in rat treated with abdominal aortic banding (AB). Results showed that tropisetron restored the desensitization of cardiac β-adrenergic receptor in AB-treated rats. In conclusion, 5-HT3 receptor antagonists protected against cardiac hypertrophy and restored the desensitization of cardiac adrenergic responsiveness, the mechanism in which may be through reducing the sympathetic activity.

Pressure overload-induced mild cardiac hypertrophy reduces left ventricular transmural differences in mitochondrial respiratory chain activity and increases oxidative stress

Objective: Increased mechanical stress and contractility characterizes normal left ventricular (LV) subendocardium (Endo) but whether Endo mitochondrial respiratory chain complex activities is reduced as compared to subepicardium (Epi) and whether pressure overload-induced LV hypertrophy (LVH) might modulate transmural gradients through increased reactive oxygen species (ROS) production is unknown. Methods: LVH was induced by 6 weeks abdominal aortic banding and cardiac structure and function were determined with echocardiography and catheterization in sham-operated and LVH rats (n = 10 for each group). Mitochondrial respiration rates, coupling, content and ROS production were measured in LV Endo and Epi, using saponin-permeabilized fibers, Amplex Red fluorescence and citrate synthase activity. Results: In sham, a transmural respiratory gradient was observed with decreases in endo maximal oxidative capacity (−36.7%, P < 0.01) and complex IV activity (−57.4%, P < 0.05). Mitochondrial hydrogen peroxide (H2O2) production was similar in both LV layers. Aortic banding induced mild LVH (+31.7% LV mass), associated with normal LV fractional shortening and end diastolic pressure. LVH reduced maximal oxidative capacity (−23.6 and −33.3%), increased mitochondrial H2O2 production (+86.9 and +73.1%), free radical leak (+27.2% and +36.3%) and citrate synthase activity (+27.2% and +36.3%) in Endo and Epi, respectively. Transmural mitochondrial respiratory chain complex IV activity was reduced in LVH (−57.4 vs. −12.2%; P = 0.02). Conclusions: Endo mitochondrial respiratory chain complexes activities are reduced compared to LV Epi. Mild LVH impairs mitochondrial oxidative capacity, increases oxidative stress and reduces transmural complex IV activity. Further studies will be helpful to determine whether reduced LV transmural gradient in mitochondrial respiration might be a new marker of a transition from uncomplicated toward complicated LVH.

Simvastatin Modulates Remodeling of Kv4.3 Expression in Rat Hypertrophied Cardiomyocytes

Hypertrophy has been shown to be associated with arrhythmias which can be caused by abnormal remodeling of the Kv4-family of transient potassium channels. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) have recently been shown to exert pleiotropic protective effects in cardiovascular diseases, including anti-arrhythmias. It is hypothesized that remodeling of Kv4.3 occurs in rat hypertrophied cardiomyocytes and is regulated by simvastatin. Male Sprague-Dawley rats and neonatal rat ventricular myocytes (NRVMs) underwent abdominal aortic banding (AAB) for 7 weeks and angiotensin II (AngII) treatment, respectively, to induce cardiac hypertrophy. Kv4.3 expression by NRVMs and myocardium (subepicardial and subendocardial) in the left ventricle was measured. The transient outward potassium current (I(to)) of NRVMs was recorded using a whole-cell patch-clamp method. Expression of the Kv4.3 transcript and protein was significantly reduced in myocardium (subepicardial and subendocardial) in the left ventricle and in NRVMs. Simvastatin partially prevented the reduction of Kv4.3 expression in NRVMs and subepicardial myocardium but not in the subendocardial myocardium. Hypertrophied NRVMs exhibited a significant reduction in the I(to) current and this effect was partially reversed by simvastatin. Simvastatin alleviated the reduction of Kv4.3 expression, I(to) currents in hypertrophied NRVMs and alleviated the reduced Kv4.3 expression in subepicardial myocardium from the hypertrophied left ventricle. It can be speculated that among the pleiotropic effects of simvastatin, the anti-arrhythmia effect is partly mediated by its effect on Kv4.3.

In Vivo and In Vitro Protective Effects of Pentamethylquercetin on Cardiac Hypertrophy

To investigate the in vivo and in vitro protective effects of pentamethylquercetin (PMQ), a member of polymethoxy flavonoids (PMFs), on cardiac hypertrophy. An in vivo cardiac hypertrophy model established by abdominal aorta banding technique in rats was treated with PMQ in increasing dosages (2.5, 5, and 10 mg x kg(-1) x d(-1)). An in vitro cardiomyocyte hypertrophy model was induced by treating neonatal cardiomyocytes with endothelin-1 (ET-1, 0.1 μM). An in vitro fibrosis model was developed in cardiac fibroblasts by aldosterone (Ald, 20 nM) and treated with PMQ (0.3, 1, 3 and 10 μM). Hemodynamic, morphological, histological, and biochemical changes were evaluated at corresponding time points. The abdominal aorta constriction (AAC) rats demonstrated a significantly elevated blood pressure and profound systolic and diastolic cardiac dysfunction. The resultant cardiac hypertrophy and heart failure were characterized by a significant increase in the heart and lung indices (3.51 ± 0.30 vs 2.35 ± 0.24, 5.58 ± 0.85 vs 3.94 ± 0.54; both P < 0.01), cardiomyocyte cross-sectional areas (153 ± 33% vs 100 ± 5%, P < 0.01) and myocardial fibrosis (9.09 ± 1.30% vs 1.49 ± 0.20%, P < 0.01) with concomitant elevation of B-type natriuretic peptide and cardiac collagen mRNA level. Daily oral administration of PMQ (2.5, 5, and 10 mg/kg for 7 weeks) prevented the foregoing histology, gene and protein changes secondary to AAC procedure. In addition, the up-regulated inflammation factors such as TNF-α and IL-6, and the down-regulated PPAR α and PPAR β were normalizd by PMQ treatment. PMQ has significant protective effects on cardiac hypertrophy through up-regulating the mRNA and protein levels of PPAR α and PPAR β involved in the process of inflammation response and cardiac fibrosis.

Abstract P229: Nongenomic Cardioprotective Effect of Dehydroepiandrosterone on Cardiac Hypertrophy: Comparison with 17β-Estradiol-Induced Cardioprotection

Objective: We recently reported a decreased σ 1 receptor expression in heart following abdominal aortic stenosis in bilateral ovariectomized (OVX) rats. Here, we demonstrated non-genemic cardioprotective effects of dehydroepiandrosterone (DHEA) though σ1 receptor in pressure overload (PO)-induced cardiac dysfunction. Methods: Bilateral ovariectomy was performed in female rats. Two weeks after the sham operation or ovariectomy, pressure-overload was initiated by abdominal aortic banding. 17β-estradiol (E2: 0.1 mg/kg) and DHEA (30 mg/kg) were administered to rats subcutaneously and orally, respectively, for 14 days starting 2 weeks after aortic banding. Hemodynamic parameters and cardiac hypertrophy were measured after 2 weeks of drug treatment. After dissection out of left ventricular, gene expression and hypertrophic signaling were analyzed by real-time RT-PCR and western blot, respectively. Results: Both E2 and DHEA treatments significantly inhibited pressure overload-induced increases both in heart weight/body weight (HW/BW) ratio and lung weight/body weight (LW/BW) ratios. Both E2 and DHEA treatments also ameliorated hypertrophy-induced impairment of left ventricular end diastolic pressure (LVEDP), left ventricular developed pressure (LVDP), left ventricular contraction and relaxation (±dp/dt) rates, heart rate (HR) and mean arterial blood pressure (MABP). Notably, DHEA but not E2 administration rescued PO-induced σ 1 receptor downregulation in left ventricular. Co-administration with NE-100, a σ 1 receptor selective antagonist, inhibited DHEA-induced amelioration of heart dysfunction without effects on E2-induced cardioprotection. Mechanistically, both E2 and DHEA treatments significantly restored PO-induced decreases in Akt phosphorylation and Akt-mediated eNOS phosphorylation (Ser1179). NE-100 treatment totally abolished DHEA-induced Akt and eNOS phosphorylation without effects on E2-induced Akt/eNOS activation. Conclusions: Taken together, based on these results with OVX rat heart, DHEA but not E2 elicits cardioprotective action through σ 1 receptor activation. DHEA-induced Akt/eNOS activation through σ 1 receptors likely mediates the cardioprotective activity.

Alteration of cardiac ACE2 expression caused by ACE inhibitor and AT 1 blockade in rats with abdominal aortic coarctation

Objective: The renin-angiotensin system (RAS) has been recognized for many years as critical pathway for blood pressure control and kidney function. Although most of the well-documented cardiovascular effects of RAS are attributed to angiotensin-converting enzyme (ACE), much less is known about the function of ACE2. The aim of this study was to investigate if the cardiac ACE2 expression changes are caused by enalapril and losartan in rats with abdominal aortic coarctation. Methods: Suprarenal abdominal aortic banding was performed as described previously in SD rats.

Effects of salviandic acid B(SA-B) on activity of basement membrane-type collagenase and impact of regulatory factors in rats with cardiac hypertrophy

To observe the effect of salviandic acid B (SA-B) on MMP-2/9 and TIMP-2 of fibrotic cardiac tissues in rats and explore the action mechanism of SA-B anti-fibrosis of heart. Ventricular remodeling model was induced by abdominal aortic banding (AAB) in rats. Rats were randomly divided into 6 groups: normal, model, SA-B high, SA-B middle, SA-B low and captopril control group. Histological changes of heart were observed with hemotoxylin and eosin (H&E) staining and Sirius red staining. Hydroxyproline (Hyp) content in heart tissue was measured by hydrolysis method. Expression of heart tissue collagen NIV, MMP-2/9 and TIMP-2 were analyzed with Western blot The activities of heart tissue MMP-2 were determined with gelatin zymography substrate degradation method. SA-B treated groups had lower heart inflammation and lower heart Hyp content; decreased Collagen deposit and alleviated cardiac fibrosis. SA-B treated groups obviously decreased the expression of Collagen IV, MMP-2/9 and TIMP-2. The activity of MMP-2 was decreased in treated SA-B treated groups. The mechanism of SA-B action against cardiac fibrosis may be related to down-regulating the expression of TIMP -2 and the activity of MMP-2/9, thus protect the normal basal membrane.

Critical Role for Stromal Interaction Molecule 1 in Cardiac Hypertrophy

Cardiomyocytes use Ca2+ not only in excitation-contraction coupling but also as a signaling molecule promoting, for example, cardiac hypertrophy. It is largely unclear how Ca2+ triggers signaling in cardiomyocytes in the presence of the rapid and large Ca2+ fluctuations that occur during excitation-contraction coupling. A potential route is store-operated Ca2+ entry, a drug-inducible mechanism for Ca2+ signaling that requires stromal interaction molecule 1 (STIM1). Store-operated Ca2+ entry can also be induced in cardiomyocytes, which prompted us to study STIM1-dependent Ca2+ entry with respect to cardiac hypertrophy in vitro and in vivo. Consistent with earlier reports, we found drug-inducible store-operated Ca2+ entry in neonatal rat cardiomyocytes, which was dependent on STIM1. Although this STIM1-dependent, drug-inducible store-operated Ca2+ entry was only marginal in adult cardiomyocytes isolated from control hearts, it increased significantly in cardiomyocytes isolated from adult rats that had developed compensated cardiac hypertrophy after abdominal aortic banding. Moreover, we detected an inwardly rectifying current in hypertrophic cardiomyocytes that occurs under native conditions (i.e., in the absence of drug-induced store depletion) and is dependent on STIM1. By manipulating its expression, we found STIM1 to be both sufficient and necessary for cardiomyocyte hypertrophy in vitro and in the adult heart in vivo. Stim1 silencing by adeno-associated viruses of serotype 9-mediated gene transfer protected rats from pressure overload-induced cardiac hypertrophy. By controlling a previously unrecognized sarcolemmal current, STIM1 promotes cardiac hypertrophy.

Effects of ischemic preconditioning on ischemia/reperfusion-induced arrhythmias by upregulatation of connexin 43 expression

BackgroundThe susceptibility of hypertrophied myocardium to ischemia-reperfusion injury is associated with increased risk of postoperative arrhythmias. We investigate the effects of ischemic preconditioning (IP) on post-ischemic reperfusion arrhythmias in hypertrophic rabbit hearts.MethodsThirty-three rabbit models of myocardial hypertrophy were randomly divided into three groups of 11 each: non-ischemia-reperfusion group (group A), ischemia-reperfusion group (group B), and ischemic preconditioning group (group C). Another ten healthy rabbits with normal myocardium served as the healthy control group. Rabbit models of myocardial hypertrophy were induced by abdominal aortic banding. Surface electrocardiogram (ECG) was recorded and Curtis-Ravingerova score was used for arrhythmia quantification. Connexin 43 (Cx43) expression was assessed by immunohistochemistry.ResultsRatios of heart weight to body weight and left ventricular weight to body weight increase significantly in the three groups compared with the healthy control group (p < 0.05). Arrhythmia incidence in group C is significantly lower than group B (p < 0.05). Curtis-Ravingerova score in group C is lower than group B (p < 0.05). Cx43 expression area in group A is smaller by comparison with the healthy control group (p < 0.05). Cx43 expression area and fluorescence intensity in group B are reduced by 60.9% and 23.9%, respectively, compared with group A (p < 0.05). In group C, Cx43 expression area increases by 32.5% compared with group B (p < 0.05), and decreases by 54.8% compared with group A (p < 0.05).ConclusionsThe incidence of ischemia/reperfusion-induced arrhythmias in hypertrophic rabbit hearts decreases after IP, which plays an important protecting role on the electrophysiology of hypertrophied myocardium by up-regulating the expression of Cx43.

Role of Adiponectin in the Development of High Fat Diet-induced Metabolic Abnormalities in Mice

The adipokine adiponectin is decreased in severe obesity and is inversely associated with adipose mass. Adiponectin is associated with insulin sensitivity and cardioprotection. Obesity frequently results in the development of a "cardiometabolic syndrome" characterized by increased circulating insulin and leptin, and cardiac hypertrophy and dysfunction. This study examined if adiponectin-deficiency affects the development of metabolic and cardiac abnormalities in response to modest obesity. Mice were studied under normal conditions and with mild cardiac pressure-overload induced by abdominal aortic banding. After surgery, wild type and adiponectin-deficient mice were fed a high-fat diet for 8 weeks (45% energy from fat vs. 10%). In wild type mice the high-fat diet increased fat and whole body mass, which corresponded with elevated circulating insulin and leptin and a decrease the glucose/insulin ratio. On the other hand, in adiponectin-deficient mice the high-fat diet had less impact on body mass and no effect on fat mass, insulin, leptin, or glucose/insulin. There was modest cardiac hypertrophy with aortic banding, but no cardiac dysfunction or effects of adiponectin deficiency or diet. The results suggest that the increase in adipose mass, leptin and insulin induced by a high fat diet is dependent on adiponectin. The lack of accelerated cardiac hypertrophy and dysfunction in the adiponectin-deficient mice subjected to aortic banding and the high-fat diet suggest that adiponectin may not play a major role in protecting the heart during the early stages of diet-induced obesity.

Sigma-1 receptor stimulation with fluvoxamine activates Akt–eNOS signaling in the thoracic aorta of ovariectomized rats with abdominal aortic banding

In the present study, we investigated the vasculoprotective effect of sigma-1 receptor stimulation with fluvoxamine on pressure overload hypertrophy-induced vascular injury in the thoracic aorta and defined mechanisms underlying that activity. Wistar rats underwent bilateral ovariectomy, and two weeks later were further treated with abdominal aortic stenosis. To confirm the vasculoprotective role of sigma-1 receptor signaling, we treated rats with the agonist fluvoxamine (at 0.5 and 1.0 mg/kg) and with the antagonist NE-100 (at1.0 mg/kg) for 4 weeks orally once a day after the onset of aortic banding. Interestingly, sigma-1 receptor expression in the thoracic aorta decreased significantly 4 weeks after pressure overload-induced hypertrophy in vehicle treated ovariectomized rats. Fluvoxamine administration significantly attenuated pressure overload-induced vascular injury with concomitant increase in receptor expression and subsequent decrease in IP3 receptor expression. Fluvoxamine treatment also significantly restored pressure overload-induced impaired Akt phosphorylation and stimulated eNOS protein expression as well as Akt-mediated eNOS phosphorylation (Ser1177). Fluvoxamine's vasculoprotective effect was nullified by co-administration of a sigma-1 receptor antagonist. No changes in phosphorylation of ERK1/2 or PKCα in the aorta were observed following pressure overload and after fluvoxamine treatment. Our findings confirm, for the first time, a potential role for sigma-1 receptor expression and signaling in the thoracic aorta in attenuating hypertrophy-induced vascular injury in ovariectomized rats. Thus, we demonstrate, for the first time, a potential role in the thoracic aorta for sigma-1 receptor expression and signaling via Akt–eNOS in attenuating hypertrophy-induced vascular injury in ovariectomized rats.