SIRT3 regulates cardiolipin biosynthesis in pressure overload-induced cardiac remodeling by PPARγ-mediated mechanism.

Cardiac remodeling is the primary pathological feature of chronic heart failure (HF). Exploring the characteristics of cardiac remodeling in the very early stages of HF and identifying targets for intervention are essential for discovering novel mechanisms and therapeutic strategies. Silent mating type information regulation 2 homolog 3 (SIRT3), as a major mitochondrial nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, is required for mitochondrial metabolism. However, whether SIRT3 plays a role in cardiac remodeling by regulating the biosynthesis of mitochondrial cardiolipin (CL) is unknown. In this study, we induced pressure overload in wild-type (WT) and SIRT3 knockout (SIRT3-/-) mice via transverse aortic constriction (TAC). Compared with WT mouse hearts, the hearts of SIRT3-/- mice exhibited more-pronounced cardiac remodeling and fibrosis, greater reactive oxygen species (ROS) production, decreased mitochondrial-membrane potential (ΔΨm), and abnormal mitochondrial morphology after TAC. Furthermore, SIRT3 deletion aggravated TAC-induced decrease in total CL content, which might be associated with the downregulation of the CL synthesis related enzymes cardiolipin synthase 1 (CRLS1) and phospholipid-lysophospholipid transacylase (TAFAZZIN). In our in vitro experiments, SIRT3 overexpression prevented angiotensin II (AngII)- induced aberrant mitochondrial function, CL biosynthesis disorder, and peroxisome proliferator-activated receptor gamma (PPARγ) downregulation in cardiomyocytes; meanwhile, SIRT3 knockdown exacerbated these effects. Moreover, the addition of GW9662, a PPARγ antagonist, partially counteracted the beneficial effects of SIRT3 overexpression. In conclusion, SIRT3 regulated PPARγ-mediated CL biosynthesis, maintained the structure and function of mitochondria, and thereby protected the myocardium against cardiac remodeling.

Antagonist of microRNA-21 improves balloon injury-induced rat iliac artery remodeling by regulating proliferation and apoptosis of adventitial fibroblasts and myofibroblasts.

Molecular pathways involved in adventitial fibroblasts (AFs) and myofibroblasts (MFs) proliferation and apoptosis contribute to vascular remodeling. MicroRNA-21 (miR-21) plays an important role in regulating cellular proliferation and apoptosis of many cell types; however, the effect of miR-21 on AFs and MFs is still unknown. In this study, we found that miR-21 was expressed in AFs and overexpressed in MFs. Inhibition of miR-21 decreased proliferation and increased apoptosis of AFs and MFs, and overexpression of miR-21 with pre-miR-21 had the reverse effect. Programmed cell death 4 (PDCD4), related to cell proliferation and apoptosis, was validated as a direct target of miR-21 by dual-luciferase reporter assay and gain and loss of function of miR-21 in AFs and MFs. PDCD4 knockdown with siRNA partly rescued the reduced proliferation with miR-21 inhibition and alleviated the increased apoptosis induced by miR-21 inhibition in AFs and MFs. Moreover, increasing PDCD4 expression by miR-21 inhibition significantly decreased JNK/c-Jun activity. In contrast, decreasing PDCD4 expression by pre-miR-21 treatment increased JNK/c-Jun activity, while the effect of miR-21 inhibition on JNK/c-Jun activity could be rescued by PDCD4 siRNA. Moreover, miR-21 inhibition could regulate proliferation and apoptosis of vascular AFs and MFs in vivo. Furthermore, miR-21 inhibition reversed vascular remodeling induced by balloon injury. In summary, our findings demonstrate that miR-21 may have a critical role in regulating proliferation and apoptosis of AFs and MFs, and PDCD4 is a functional target gene involved in the miR-21-mediated cellular effects in vascular remodeling by a miR-21/PDCD4/JNK/c-Jun pathway.

Association between human cartilage glycoprotein 39 (YKL-40) and arterial stiffness in essential hypertension.

BACKGROUND: YKL-40, a proposed marker of inflammation and endothelial dysfunction, is associated with atherosclerosis and an increased cardiovascular mortality in the general population. However, the relationship between YKL-40 and arterial stiffness in hypertensive patients has not been adequately assessed. METHODS: The relationship between serum levels of YKL-40 and arterial stiffness was evaluated in 93 essential hypertensive subjects and 80 normal subjects. Essential hypertensive subjects were divided into two groups based upon urinary albumin-to-creatinine ratio (ACR): nonmicroalbuminuric group, (ACR <30 mg/g, n = 50) and microalbuminuric group (ACR ≥ 30 mg/g, n = 43). Large artery wall stiffness was assessed by measuring femoral arterial stiffness and carotid-femoral pulse wave velocity (cf-PWV). Serum levels of YKL-40 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The study demonstrated that YKL-40,cf-PWV and femoral arterial stiffness were increased significantly (P<0.05) in the hypertensive group compared with normal controls. These measurements were also increased significantly ( P<0.05) in the microalbuminuric group compared with the nonmicroalbuminuric group. YKL-40 was positively correlated with cf-PWV( r = 0.44, P = 0.000) and femoral arterial stiffness ( r = 0.42, P =0.001). Multiple linear stepwise regression analysis showed that YKL-40 was the impact factor of arterial stiffness ( P<0.05). CONCLUSION: YKL-40 levels are elevated in essential hypertension subjects with an independent association between increasing YKL-40 levels and increasing arterial stiffness. The study suggests it played a positive role of YKL-40 in the progressing vascular complications in patients with essential hypertension.

Simvastatin exerts cardioprotective effects and inhibits the activity of Rho-associated protein kinase in rats with metabolic syndrome.

1. Insulin resistance (IR) is crucially involved in the pathophysiology of metabolic syndrome (MS). The aim of the present study was to investigate the effects of simvastatin on IR in rats with MS. 2. A rat model of MS was established and myocardial damage was examined by transmission electron microscopy. Twenty-two MS rats were divided into two groups of 11 rats each: (i) an MS group; and (ii) a simvastatin-treated MS. Ten Wistar rats were used as controls. The phosphorylation of myosin phosphatase target subunit 1 (MYPT-1), insulin receptor substrate 1 (IRS-1) and Akt were analysed by immunohistochemistry and western blotting. 3. Insulin resistance-induced MS was associated with a significant increase in Rho kinase (ROCK) activity and inhibition of the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. Decreased levels of phosphorylated (p-) MYPT-1 and p-IRS-1 (Ser³°7) and increased levels of p-Akt were found in hearts from the MS + simvastatin compared with the MS group. These results suggest that simvastatin reduces ROCK activity and increases Akt activity. 4. Simvastatin exerts cardioprotective effects and improves IR, which can be attributed, at least in part, to the inhibition of ROCK and activation of PI3-K/Akt.

CRP enhances soluble LOX-1 release from macrophages by activating TNF-α converting enzyme.

Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. We hypothesized that the inflammatory marker C-reactive protein (CRP) might stimulate sLOX-1 release by activating tumor necrosis factor-α converting enzyme (TACE). Macrophages differentiated from THP-1 cells were stimulated with TNF-α and further treated with CRP in the absence or presence of specific inhibitors or small interfering RNA (siRNA). Our results showed that CRP increased sLOX-1 release from activated macrophages in a dose-dependent manner and that these effects were regulated by Fc γ receptor II (FcγRII)-mediated p47(phox) phosphorylation, reactive oxygen species (ROS) production, and TACE activation. CRP also enhanced sLOX-1 release from macrophages derived from peripheral blood mononuclear cells (PBMC) of patients with acute coronary syndrome (ACS). Pretreatment with antibody against FcγRII or with CD32 siRNA, p47(phox) siRNA, apocynin, N-acetylcysteine, tumor necrosis factor-α protease inhibitor 1 (TAPI-1) or TACE siRNA attenuated sLOX-1 release induced by CRP. CRP also elevated serum sLOX-1 levels in a rabbit model of atherosclerosis. Thus, CRP might stimulate sLOX-1 release, and the underlying mechanisms possibly involved FcγRII-mediated p47(phox) phosphorylation, ROS production, and TACE activation.

2019 Chinese Hypertension League guidelines on home blood pressure monitoring.

In China, automated blood pressure monitors have been readily available for home use. Home blood pressure monitoring has been indispensable in the management of hypertension. There is therefore a need to establish guidelines for home blood pressure monitoring on the basis of the 2012 consensus document. In this guidelines document, the committee put forward recommendations on the selection and calibration of blood pressure measuring devices, the frequency (times) and duration (days) of blood pressure measurement, and the diagnostic threshold of home blood pressure.

Effects and mechanisms of PPARalpha activator fenofibrate on myocardial remodelling in hypertension.

Although peroxisome proliferator-activated receptor alpha (PPARalpha) is highly expressed in the heart, the effects of PPARalpha on cardiac remodelling and the underlying mechanisms are unclear. The present study was undertaken to test the hypothesis that PPARalpha activator fenofibrate plays a key role in left ventricular hypertrophic remodelling via the formation of c-fos/c-jun heterodimers in spontaneous hypertensive rats (SHRs). Twenty-four male 8-week-old SHRs were randomly divided into two groups, one group treated with oral saline (n= 10) and another treated with oral fenofibrate (60 mg.kg-1.d-1, n= 14). Ten same-aged Wistar-Kyoto (WKY) rats were selected as a normal control group. Using echocardiography, immunohistochemistry, co-immunoprecipitation, Western blot analysis and real-time RT-PCR, we showed that the left ventricular wall thickness and significantly reduced and left ventricular diastolic function improved in SHRs treated with fenofibrate compared with SHRs treated with saline. Similarly, the excessive collagen deposition and the up-regulation of collagen I, collagen III, c-fos and c-jun seen in SHRs receiving saline were significantly attenuated in SHRs receiving fenofibrate. In addition, fenofibrate markedly decreased the expression of AP-1 and c-fos/c-jun heterodimers (P < 0.01). These results demonstrated that PPARalpha activator fenofibrate may exert a protective effect on cardiac remodelling in SHRs by decreasing the expression of c-fos and c-jun and suppressing the formation of c-fos/c-jun heterodimers, which may further inhibit transcription of the downstream genes involved in the pathogenesis of left ventricular hypertrophy induced by hypertension.

Tong-xin-luo capsule inhibits left ventricular remodeling in spontaneously hypertensive rats by enhancing PPAR-gamma expression and suppressing NF-kappaB activity.

BACKGROUND: Tong-xin-luo capsule (TXL), used as a traditional Chinese herb, offeres a therapeutic potential for treatment of cardiovascular diseases. It has been shown to exert a variety of pharmacological effects, including antihypertensive effects, and is able to improve ventricular remodeling. However, the mechanisms of its action are not completely understood. The aim of this study was to evaluate the molecular mechanisms of Tong-xin-luo capsule on left ventricular remodeling in spontaneously hypertensive rats (SHR). METHODS: Sixteen eight-week-old SHRs were randomized into an SHR group (n = 8) and a TXL group (n = 8) that were given Tong-xin-luo capsule (1.5 mg x kg(-1) x d(-1)). Eight Wistar Kyoto (WKY) rats fed with 0.9% NaCl served as the control group (WKY group). Systolic blood pressure (BP), body weight and heart rate were monitored once every two weeks. Ventricular remodeling was detected by histopathological examination. Nuclear factor kappa B P65 (NF-kappaB P65) and peroxisome proliferators activated receptor gamma (PPAR-gamma) protein and phosphorylated inhibitor kappa alpha (IkappaBalpha) protein were detected by immunohistochemistry and western blot respectively. The physical interaction of the P65-P50 heterodimer with IkappaBalpha and NF-kappaB were measured by co-immunoprecipitation. PPAR-gamma mRNA, collagen I mRNA and collagen III mRNA were measured by real-time PCR. RESULTS: TXL inhibited NF-kappaB P65 expression and ventricular remodeling and suppressed the activation of NF-kappaB compared with the SHR group (P < 0.01, P < 0.05). TXL reduced IkappaBalpha phosphorylation, increased expression of PPAR-gamma protein and enhanced the physical interaction of the P65-P50 heterodimer with IkappaBalpha. The mRNA expression of PPAR-gamma was enhanced but the mRNA expression of collagen I mRNA and collagen I mRNA were suppressed by TXL. CONCLUSIONS: In spontaneously hypertensive rats, TXL could inhibit ventricular remodeling induced by hypertension, and the inhibitory effect might be associated with the process of TXL increasing the expression of PPAR-gamma that could result in the inhibition of the activation of NF-kappaB.

HGF Reduces Disease Severity and Inflammation by Attenuating the NF-κB Signaling in a Rat Model of Pulmonary Artery Hypertension.

The purpose of the present study was to investigate the anti-inflammatory effect of hepatocyte growth factor (HGF) on pulmonary artery hypertension (PAH) in a rat model and underlying mechanisms. Wistar rats were treated with monocrotaline intravenously to induce PAH and then treated with vehicle or HGF for 2 weeks, respectively. The mean pulmonary artery pressure (mPAP), the index of right heart ventricular hypertrophy (RHVI), pathological changes, and inflammation in the lungs of individual rats were measured. The levels of serum inflammatory interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and high mobility group protein B1 (HMGB1) and the relative levels of IκBα and NF-κB p65 expression in the lungs of individual rats were determined by methods of enzyme-linked immunosorbent assay (ELISA) and Western blot. The levels of mPAP and RVHI in the HGF group were significantly lower than that in the PAH group (P < 0.05), but remained significantly higher than that of the control group (P < 0.05). Similar patterns of inflammatory scores and the levels of serum IL-6, TNF-α, ICAM-1, and HMGB1 were detected among the different groups of rats. Furthermore, the relative levels of IκBα expression in the lungs of the HGF group of rats were significantly higher than that in the control group, which were significantly higher than that in the PAH group. In contrast, the relative levels of NF-kB p65 expression in the HGF group were significantly lower than that in the PAH group (P < 0.05). HGF treatment significantly mitigated the severity of PAH and inhibited inflammation by attenuating the NF-kB signaling in the lungs of PAH rats.

In vitro, ex vivo and in vivo anti-hypertensive activity of Chrysophyllum cainito L. extract.

Chrysophyllum cainito L., a traditional herbal medicine, could have the potential for management of hypertension due to presence of polyphenolic compounds. The extracts and fractions of the pulp of plant were evaluated for in vitro (inhibition of angiotensin I converting enzyme/ACE assay), ex vivo (isolated aorta relaxation assay) and in vivo (salt induced hypertensive rat assay). The alcoholic and aqueous extract (ALE and AQE respectively) of fruit of plant C. cainito was having 14.8 and 9.2% yield respectively. The fractionation with ethyl alcohol (EAF) and butanol (BTF) yielded 2.52 & 2.17% respectively from ALE and 0.46 & 0.31% respectively from AQE with respect to fruit pulp dry weight. More phenolic content was found in ALE (3.75±0.15 mg gallic acid equivalent or GAE g(-1) of dry power of fruit pulp) compared to AQE and maximum in ethyl acetate fraction of ALE (ALE-EAF) (2.32±0.21 mg GAE g(-1) of dry power of fruit pulp) among all fractions. ACE inhibition activity was found to be maximum in ALE-EAF 62.5±7.34%. While ex vivo study using isolated tissue of aorta showed again showed maximum activity (62.82±6.19 and 46.47±8.32% relaxation with 50 µg mL(-1) and 10 µg mL(-1) GAE concentration respectively). ALE-EAF reduced the elevated arterial pressure of salt induced hypertensive rat significantly to the level of normotensive animal group. Results of ALE-EAF have shown its potential as a source for novel constituent for the treatment hypertension and should further be studied for isolation of specific constituent for more effectiveness.

Role of endogenous PDGF-BB in cultured cardiomyocytes exposed to hypoxia.

Platelet-derived growth factor-BB (PDGF-BB) plays a critical role in cell proliferation, angiogenesis and fibrosis. However, its exact role in cardiomyocytes exposed to hypoxia is not well known. This study was therefore designed to detect whether PDGF-BB expression was changed in a hypoxic condition, then the possible role of endogenous PDGF-BB in cardiomyocytes was explored, with interference RNA in a lentiviral vector ex vivo. The results showed that cultured cardiomyocytes exhibited an optimal proliferation from 3 to 10 days. However, LDH level was significantly increased but the heart rhythm was not altered in cardiomyocytes exposed to hypoxia for 24 hours. PDGF-BB expression was substantially upregulated in hypoxic cardiomyocytes. In order to know the role of PDGF-BB, we performed PDGF-BB knockdown in cultured cardiomyocytes. The number of apoptotic cells and the level of LDH were significantly increased but the beat rhythm was reduced in cardiomyocytes with PDGF-BB knockdown. These findings suggest that endogenous PDGF-BB exerts a crucial protective effect to cultured cardiomyocytes exposed to hypoxia.

Huang-lian-jie-du-tang protects rats from cardiac damages induced by metabolic disorder by improving inflammation-mediated insulin resistance.

Huang-lian-jie-du-tang (HLJDT), a traditional Chinese medicine, has been shown to improve insulin resistance (IR) induced by inflammation, a key event in the development of metabolic syndrome (MS). The present study aimed to investigate the protective effects of HLJDT on MS and explore the underlying mechanism. MS rats were established with obese-diets and treated with normal saline, aspirin or HLJDT. The myocardial lesions were identified by echocardiogram, transmission electron microscope, and Sirius-red staining. The inflammatory cytokines were measured by ELISA and real-time PCR. The activation of NF-κB, JNK, SOCS3, IRS1 and AKT in the heart was detected by immunohistochemistry and Western blot analysis. Compared with the controls, MS rats developed obvious obesity, hypertension, dyslipidemia, IR, inflammation, and cardiac damage. Moreover, phosphorylated IRS-1 at Ser307 was correlated with the activation of NF-κB, JNK and SOCS3 and the inhibition of AKT in the heart from MS rats. These data suggest that serine phosphorylation of IRS-1 in response to inflammation is mediated, in part, by NF-κB, JNK and SOCS3. Notably, HLJDT inhibited the activation of NF-κB and reduced serine phosphorylation of IRS-1. In summary, HLJDT protects myocardium from IR-mediated injury by inhibiting serine phosphorylation of IRS-1 in MS rats.

[Expression of SIRT1 in right auricle tissues and the relationship with oxidative stress in patients with atrial fibrillation].

AIM: To observe the expression of mammalian sirtuin 1 (SIRT1) in right auricle tissues in patients presenting with atrial fibrillation (AF) and make clear the relationship between SIRT1 expression and oxidative stress. METHODS: A total of 38 patients with rheumatic heart disease were divided into 2 groups: AF group (AF lasted more than 6 months, n=25) and SR (sinus rhythm) group (n=13). The expression of SIRT1 in right auricle tissues harvested during heart operations was detected by immunohistochemistry. Oxidative stress was estimated by the amounts of malondialdehyde (MDA) and metallothionein (MT) and the activity of superoxide dismutase (SOD) which were detected using thiobarbituric acid reaction (TBA), enzyme-linked immunosorbent assay (ELISA) and xanthine oxidase assay, respectively. RESULTS: Compared with the SR group, the expression of SIRT1 protein in the atrium significantly increased in AF group [P<0.05, (45.8±4.03)% vs (19.7±2.54)%]. In AF group, MDA was (7.24±1.05) nmol/mg, SOD (1034.25±84.32) U/mg and MT (7.21±1.46) µg/g, all being significantly higher than those in SR group[P<0.05, MDA: (3.01±0.47) nmol/mg; SOD: (723.63±65.23) U/mg; MT: (4.31±1.23) µg/g]. Spearman correlation indicated that the expression of SIRT1 had a significantly negative correlation with the amounts of MDA and MT and the activity of SOD (P<0.05, r=-0.447, -0.521, -0.394, respectively). CONCLUSION: The expression of SIRT1 increased in patients with AF. SIRT1 maybe effects the AF by means of inhibiting the process of oxidative stress.

Myocardial remodeling in rats with metabolic syndrome: role of Rho-kinase mediated insulin resistance.

Insulin resistance (IR) plays a critical role in metabolic syndrome (MS). Previous studies have demonstrated that activated ROCK is increased in MS patients. However, the effect of Rho-kinase (ROCK) on IR has not been definitely determined. Thus, the aims of the present study were to determine whether ROCK activation induces IR or affects myocardial structure and function, as well as the possible mechanisms underlying this process. Wistar rats fed high fat, high glucose and high salt diet sewed as model of MS and we used transmission electron microscopy, echocardiogram technology, and terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling staining to identify any myocardial damage. The protein levels of MYPT-1 (characteristic of ROCK activation), IRS-1 and AKT were analyzed by immunohistochemistry and Western blotting. In hearts from MS rats, we found increased protein levels of phospho-MYPT-1 and phospho-IRS-1 (Ser307) and decreased phospho-AKT compared to levels in normal rats. In conclusion, the results suggest that ROCK-mediated IR is involved in the development of myocardial impairments in MS rats and that this effect is mediated probably via the IRS-1/PI3-kinase/AKT pathway.

Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats.

Rosiglitazone, an important peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, improves left ventricular (LV) hypertrophy in diet-induced hypercholesterolemic rats. However, the effects and underlying mechanisms of rosiglitazone on myocardial remodeling in spontaneous hypertension rats (SHRs) are unclear. Twenty male 8-week-old SHRs were randomly divided into two groups: one treated with oral saline (n=10) and the other treated with rosiglitazone (5 mgkg(-1)day(-1), n=10). Ten age-matched Wistar-Kyoto rats were selected as a normal control group. Echocardiography, immunohistochemistry, real-time reverse transcriptase-PCR and western blot analysis were performed to assess the effects of rosiglitazone. After 16 weeks of treatment, LV hypertrophy was significantly attenuated by rosiglitazone (LV weight/body weight, 2.35±0.11 vs. 2.56±0.14 mgg(-1)). According to the echocardiography results, thickening of the LV wall was reduced, and mid-wall fractional shortening was improved by rosiglitazone. Similarly, the excessive collagen deposition and upregulation of collagen I and collagen III seen in SHRs receiving saline were significantly attenuated in SHRs receiving rosiglitazone. In addition, rosiglitazone treatment increased the activity of matrix metalloproteinase-9 (MMP-9) and normalized the MMP-9/tissue inhibitor of metalloproteinase-1 ratio. Furthermore, activator protein-1 (AP-1) activation and nuclear factor-kappa B (NF-κB) expression were suppressed in the rosiglitazone-treated group. These results demonstrate that the PPAR-γ agonist rosiglitazone had beneficial effects on myocardial remodeling in SHRs by way of decreasing AP-1 activation and NF-κB expression, which may help in further inhibiting transcription of the downstream genes involved in the pathogenesis of myocardial remodeling induced by hypertension.

TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model.

OBJECTIVE: Tribbles 3 (TRB3) is associated with insulin resistance, an important trigger in the development of diabetic cardiomyopathy (DCM). We sought to determine whether TRB3 plays a major role in modulating DCM and the mechanisms involved. RESEARCH DESIGN AND METHODS: The type 2 diabetic rat model was induced by high-fat diet and low-dose streptozotocin. We evaluated the characteristics of type 2 DCM by serial echocardiography and metabolite tests, Western blot analysis for TRB3 expression, and histopathologic analyses of cardiomyocyte density, lipids accumulation, cardiac inflammation, and fibrosis area. We then used gene silencing to investigate the role of TRB3 in the pathophysiologic features of DCM. RESULTS: Rats with DCM showed severe insulin resistance, left ventricular dysfunction, aberrant lipids deposition, cardiac inflammation, fibrosis, and TRB3 overexpression. We found that the silencing of TRB3 ameliorated metabolic disturbance and insulin resistance; myocardial hypertrophy, lipids accumulation, inflammation, fibrosis, and elevated collagen I-to-III content ratio in DCM rats were significantly decreased. These anatomic findings were accompanied by significant improvements in cardiac function. Furthermore, with TRB3 gene silencing, the inhibited phosphorylation of Akt was restored and the increased phosphorylation of extracellular signal-regulated kinase 1/2 and Jun NH(2)-terminal kinase in DCM was significantly decreased. CONCLUSIONS: TRB3 gene silencing may exert a protective effect on DCM by improving selective insulin resistance, implicating its potential role for treatment of human DCM.