Irisin inhibits high glucose‐induced endothelial‐to‐mesenchymal transition and exerts a dose‐dependent bidirectional effect on diabetic cardiomyopathy

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes‐induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r‐irisin (low or high dose: 0.5 or 1.5 μg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low‐dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high‐dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low‐dose irisin involved irisin‐mediated inhibition of high glucose‐induced endothelial‐to‐mesenchymal transition (EndMT); conversely, high‐dose irisin treatment enhanced high glucose‐induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low ‐ dose irisin alleviated DCM development by inhibiting high glucose‐induced EndMT. By contrast, high‐dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose‐induced EndMT and exert a dose‐dependent bidirectional effect on DCM.     

Diabetes influences cardiac extracellular matrix remodelling after myocardial infarction and subsequent development of cardiac dysfunction

This study was conducted to examine the influence of acute streptozotocin‐induced diabetes on cardiac remodelling and function in mice subjected to myocardial infarction (MI) by coronary artery ligation. Echocardiography analysis indicated that diabetes induced deleterious cardiac functional changes as demonstrated by the negative differences of ejection fraction, fractional shortening, stroke volume, cardiac output and left ventricular volume 24 hrs after MI. Temporal analysis for up to 2 weeks after MI showed higher mortality in diabetic animals because of cardiac wall rupture. To examine extracellular matrix remodelling, we used fluorescent molecular tomography to conduct temporal studies and observed that total matrix metalloproteinase (MMP) activity in hearts was higher in diabetic animals at 7 and 14 days after MI, which correlated well with the degree of collagen deposition in the infarct area visualized by scanning electron microscopy. Gene arrays indicated temporal changes in expression of distinct MMP isoforms after 1 or 2 weeks after MI, particularly in diabetic mice. Temporal changes in cardiac performance were observed, with a trend of exaggerated dysfunction in diabetic mice up to 14 days after MI. Decreased radial and longitudinal systolic and diastolic strain rates were observed over 14 days after MI, and there was a trend towards altered strain rates in diabetic mouse hearts with dyssynchronous wall motion clearly evident. This correlated with increased collagen deposition in remote areas of these infarcted hearts indicated by Masson's trichrome staining. In summary, temporal changes in extracellular matrix remodelling correlated with exaggerated cardiac dysfunction in diabetic mice after MI.     

Hyperglycemia and angiotensin II cooperate to enhance collagen I deposition by cardiac fibroblasts through a ROS-STAT3-dependent mechanism

Cardiac fibroblasts significantly contribute to diabetes-induced structural and functional changes in the myocardium. The objective of the present study was to determine the effects of high glucose (alone or supplemented with angiotensin II) in the activation of the JAK2/STAT3 pathway and its involvement in collagen I production by cardiac fibroblasts. We observed that the diabetic environment 1) enhanced tyrosine phosphorylation of JAK2 and STAT3; 2) induced nuclear localization of tyrosine phosphorylated STAT3 through a reactive oxygen species-mediated mechanism, with angiotensin II stimulation further enhancing STAT3 nuclear accumulation; and 3) stimulated collagen I production. The effects were inhibited by depletion of reactive oxygen species or silencing of STAT3 in high glucose alone or supplemented with exogenous angiotensin II. Combined, our data demonstrate that increased collagen I deposition in the setting of high glucose occurred through a reactive oxygen species- and STAT3-dependent mechanism. Our results reveal a novel role for STAT3 as a key signaling molecule of collagen I production in cardiac fibroblasts exposed to a diabetic environment.     

High glucose promotes the production of collagen types I and III by cardiac fibroblasts through a pathway dependent on extracellular-signal-regulated kinase 1/2

Hyperglycemia promotes fibrosis by increasing collagen synthesis, a process involving mitogen activated protein kinases (MAPKs). Several studies of diabetic cardiomyopathy have demonstrated an accumulation of collagen, including collagen types I and III, in the myocardium, leading to interstitial fibrosis, which is related to left-ventricular diastolic dysfunction. However, the mechanisms of hyperglycemia-induced collagen production in cardiac fibroblasts are poorly defined. In the present study, neonatal rat cardiac fibroblasts treated with high glucose (25 mM) were assessed by real time PCR and enzyme linked immunosorbent assay (ELISA) showed an increase in both the mRNA and protein level of collagen types I and III. These effects were not due to changes in osmotic pressure. Extracellular signal regulated kinase 1/2 (ERK1/2) was activated by high glucose level (25 mM), and treatment with PD98059 to block ERK phosphorylation significantly inhibited the mRNA and protein expression of collagen types I and III. These results suggest that high glucose accelerates the synthesis of collagen types I and III, and an ERK1/2 cascade in cardiac fibroblasts play an essential role in the control of collagen deposition by high glucose.     

Iuteolin对糖尿病大鼠心脏功能的保护作用及其可能机制

目的：研究Iuteolin对链脲佐菌素诱导的Ⅰ型糖尿病大鼠心功能及心肌线粒体氧化应激的影响。方法：雄性SD大鼠,随机分成正常对照组,Iuteolin对照纽,糖尿病模型组,低剂量Iuteolin（10ms／（kg·d））灌胃治疗组,高剂量Iuteolin（100ms／（kg·d））灌胃治疗组。各组大鼠饲养8周后,测体重、血糖、心功能、左心室重量、心肌胶原含量及活性氧自由基（ROS）水平,分离心肌线粒体检测ROS水平、超氧化物歧化酶（SOD）活性及线粒体肿胀程度。结果：Iuteolin处理对糖尿病大鼠血糖无明显影响,但可减少糖尿病引起的体重下降。高剂量Iuteolin可显著减小糖尿病大鼠心室与体重比值,提高左室发展压,降低左室舒张末压。高剂量Iuteolin治疗后,糖尿病大鼠心肌ROS及胶原含量。心肌线粒体ROS水平与肿胀程度均明显下降,心肌线粒体SOD活性明显增加。结论：Iuteolin处理可显著改善糖尿病大鼠心功能．其机制可能与减轻心肌线粒体氧化应激及抑制线粒体肿胀有关。     

Osteocrin,a novel myokine,prevents diabetic cardiomyopathy via restoring proteasomal activity

Proteasomal activity is compromised in diabetic hearts that contributes to proteotoxic stresses and cardiac dysfunction. Osteocrin (OSTN) acts as a novel exercise-responsive myokine and is implicated in various cardiac diseases. Herein, we aim to investigate the role and underlying molecular basis of OSTN in diabetic cardiomyopathy (DCM). Mice received a single intravenous injection of the cardiotrophic adeno-associated virus serotype 9 to overexpress OSTN in the heart and then were exposed to intraperitoneal injections of streptozotocin (STZ, 50 mg/kg) for consecutive 5 days to generate diabetic models. Neonatal rat cardiomyocytes were isolated and stimulated with high glucose to verify the role of OSTN in vitro. OSTN expression was reduced by protein kinase B/forkhead box O1 dephosphorylation in diabetic hearts, while its overexpression significantly attenuated cardiac injury and dysfunction in mice with STZ treatment. Besides, OSTN incubation prevented, whereas OSTN silence aggravated cardiomyocyte apoptosis and injury upon hyperglycemic stimulation in vitro. Mechanistically, OSTN treatment restored protein kinase G (PKG)-dependent proteasomal function, and PKG or proteasome inhibition abrogated the protective effects of OSTN in vivo and in vitro. Furthermore, OSTN replenishment was sufficient to prevent the progression of pre-established DCM and had synergistic cardioprotection with sildenafil. OSTN protects against DCM via restoring PKG-dependent proteasomal activity and it is a promising therapeutic target to treat DCM.Subject terms: Proteasome, Heart failure     

头顶一颗珠提取液对实验性糖尿病大鼠心肌损伤的干预作用

目的：探讨头顶一颗珠提取液（TTM）对糖尿病大鼠心肌损伤的干预作用及机制,为进一步研究头顶一颗珠的药理作用提供理论基础。方法：雄性SPF级SD大鼠48只,随机分为4组（n=12）正常对照组、模型组、干预组、及阳性对照组,采用高脂饮食加一次性尾静脉注射STZ 35 mg/kg复制糖尿病模型。干预组在实验开始时给予TTM浓度1 mg/ml头顶一颗珠提取液3 ml灌胃,每天1次;造模成功后阳性对照组用二甲双胍5mg/kg.d灌胃治疗,各组继续喂养6周,处死大鼠,取血测B型脑钠肽（BNP）、心肌肌钙蛋白I（cTnI）水平,心脏称重计算心脏重量指数（心重/体重）,TUNEL法计算心肌细胞凋亡指数,取心室肌组织行常规形态学及Masson染色观察,检测心肌组织SOD, GPx,MDA水平。结果：TTM干预可明显降低糖尿病大鼠心脏重量,降低血清中BNP、cTnI水平,提高心肌组织中SOD, GPx活性,降低MDA含量,抑制心肌细胞凋亡,而且在增强GPx活性、抑制胶原纤维产生方面,TTM作用比西药二甲双胍效果更好。结论：头顶一颗珠提取物可能通过减轻糖尿病大鼠体内氧化应激反应,进而抑制心肌细胞凋亡,减少胶原纤维产生,来达到保护心肌细胞损伤的作用。     

FGF21 deletion exacerbates diabetic cardiomyopathy by aggravating cardiac lipid accumulation

Fibroblast growth factor 21 (FGF21) plays an important role in energy homoeostasis. The unaddressed question of FGF21's effect on the development and progression of diabetic cardiomyopathy (DCM) is investigated here with FGF21 knockout (FGF21KO) diabetic mice. Type 1 diabetes was induced in both FGF21KO and C57BL/6J wild‐type (WT) mice via streptozotocin. At 1, 2 and 4 months after diabetes onset, the plasma FGF21 levels were significantly decreased in WT diabetic mice compared to controls. There was no significant difference between FGF21KO and WT diabetic mice in blood glucose and triglyceride levels. FGF21KO diabetic mice showed earlier and more severe cardiac dysfunction, remodelling and oxidative stress, as well as greater increase in cardiac lipid accumulation than WT diabetic mice. Western blots showed that increased cardiac lipid accumulation was accompanied by further increases in the expression of nuclear factor (erythroid‐derived 2)‐like 2 (Nrf2) and its target protein CD36, along with decreases in the phosphorylation of AMP‐activated protein kinase and the expression of hexokinase II and peroxisome proliferator‐activated receptor gamma co‐activator 1α in the heart of FGF21KO diabetic mice compared to WT diabetic mice. Our results demonstrate that FGF21 deletion‐aggravated cardiac lipid accumulation is likely mediated by cardiac Nrf2‐driven CD36 up‐regulation, which may contribute to the increased cardiac oxidative stress and remodelling, and the eventual development of DCM. These findings suggest that FGF21 may be a therapeutic target for the treatment of DCM.     

Dapagliflozin alleviates cardiac fibrosis through suppressing EndMT and fibroblast activation via AMPKα/TGF-β/Smad signalling in type 2 diabetic rats

Diabetic cardiomyopathy (DCM) is one of the leading causes of heart failure in patients with diabetes mellitus, with limited effective treatments. The cardioprotective effects of sodium-glucose cotransporter 2(SGLT2) inhibitors have been supported by amounts of clinical trials, which largely fills the gap. However, the underlying mechanism still needs to be further explored, especially in terms of its protection against cardiac fibrosis, a crucial pathophysiological process during the development of DCM. Besides, endothelial-to-mesenchymal transition (EndMT) has been reported to play a pivotal role in fibroblast multiplication and cardiac fibrosis. This study aimed to evaluate the effect of SGLT2 inhibitor dapagliflozin (DAPA) on DCM especially for cardiac fibrosis and explore the underlying mechanism. In vivo, the model of type 2 diabetic rats was built with high-fat feeding and streptozotocin injection. Untreated diabetic rats showed cardiac dysfunction, increased myocardial fibrosis and EndMT, which was attenuated after treatment with DAPA and metformin. In vitro, HUVECs and primary cardiac fibroblasts were treated with DAPA and exposed to high glucose (HG). HG-induced EndMT in HUVECs and collagen secretion of fibroblasts were markedly inhibited by DAPA. Up-regulation of TGF-β/Smad signalling and activity inhibition of AMPKα were also reversed by DAPA treatment. Then, AMPKα siRNA and compound C abrogated the anti-EndMT effects of DAPA in HUVECs. From above all, our study implied that DAPA can protect against DCM and myocardial fibrosis through suppressing fibroblast activation and EndMT via AMPKα-mediated inhibition of TGF-β/Smad signalling.     

H3 relaxin inhibits the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose

Excessive production of reactive oxygen species (ROS) and P2X7R activation induced by high glucose increases NLRP3 inflammasome activation, which contributes to the pathogenesis of diabetic cardiomyopathy. Although H3 relaxin has been shown to inhibit cardiac fibrosis induced by isoproterenol, the mechanism has not been well studied. Here, we demonstrated that high glucose (HG) induced the collagen synthesis by activation of the NLRP3 inflammasome, leading to caspase‐1 activation, interleukin‐1β (IL‐1β) and IL‐18 secretion in neonatal rat cardiac fibroblasts. Moreover, we used a high‐glucose model with neonatal rat cardiac fibroblasts and showed that the activation of ROS and P2X7R was augmented and that ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation was critical for the collagen synthesis. Inhibition of ROS and P2X7R decreased NLRP3 inflammasome‐mediated collagen synthesis, similar to the effects of H3 relaxin. Furthermore, H3 relaxin reduced the collagen synthesis via ROS‐ and P2X7R‐mediated NLRP3 inflammasome activation in response to HG. These results provide a mechanism by which H3 relaxin alleviates NLRP3 inflammasome‐mediated collagen synthesis through the inhibition of ROS and P2X7R under HG conditions and suggest that H3 relaxin represents a potential drug for alleviating cardiac fibrosis in diabetic cardiomyopathy.     

Ginsenoside Rg1 ameliorates diabetic cardiomyopathy by inhibiting endoplasmic reticulum stress‐induced apoptosis in a streptozotocin‐induced diabetes rat model

Ginsenoside Rg1 has been demonstrated to have cardiovascular protective effects. However, whether the cardioprotective effects of ginsenoside Rg1 are mediated by endoplasmic reticulum (ER) stress‐induced apoptosis remain unclear. In this study, among 80 male Wistar rats, 15 rats were randomly selected as controls; the remaining 65 rats received a diet rich in fat and sugar content for 4 weeks, followed by intraperitoneal injection of streptozotocin (STZ, 40 mg/kg) to establish a diabetes model. Seven days after STZ injection, 10 rats were randomly selected as diabetic model (DM) controls, 45 eligible diabetic rats were randomized to three treatment groups and administered ginsenoside Rg1 in a dosage of 10, 15 or 20 mg/kg/day, respectively. After 12 weeks of treatment, rats were killed and serum samples obtained to determine cardiac troponin (cTn)‐I. Myocardial tissues were harvested for morphological analysis to detect myocardial cell apoptosis, and to analyse protein expression of glucose‐regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), and Caspase‐12. Treatment with ginsenoside Rg1 (10–20 mg/kg) significantly reduced serum cTnI levels compared with DM control group (all P < 0.01). Ginsenoside Rg1 (15 and 20 mg/kg) significantly reduced the percentage of apoptotic myocardial cells and improved the parameters of cardiac function. Haematoxylin and eosin and Masson staining indicated that ginsenoside Rg1 could attenuate myocardial lesions and myocardial collagen volume fraction. Additionally, ginsenoside Rg1 significantly reduced GRP78, CHOP, and cleaved Caspase‐12 protein expression in a dose‐dependent manner. These findings suggest that ginsenoside Rg1 appeared to ameliorate diabetic cardiomyopathy by inhibiting ER stress‐induced apoptosis in diabetic rats.     

Beneficial effect of nitric oxide synthase inhibitor on hepatotoxicity induced by allyl alcohol

The effect of aminoguanidine (a selective inhibitor of inducible nitric oxide synthase) on allyl alcohol-induced liver injury was assessed by the measurement of serum ALT and AST activities and histopathological examination. When aminoguanidine (50-300 mg/kg, i.p.) was administered to mice 30 min before a toxic dose of allyl alcohol (75 microL/kg, i.p.), significant changes related to liver injury were observed. In the presence of aminoguanidine the level of ALT and AST enzymes were significantly decreased. All symptoms of liver necrosis produced by allyl alcohol toxicity almost completely disappeared when animals were pretreated with aminoguanidine at 300 mg/kg. Depletion of hepatic glutathione as a consequence of allyl alcohol metabolism was minimal in mice pretreated with aminoguanidine at 300 mg/kg. It was found that the inhibition of toxicity was not due to alteration in allyl alcohol metabolism since aminoguanidine did not effect alcohol dehydrogenase activity both in vivo and in vitro.     

In vitro glycation of a tissue-engineered wound healing model to mimic diabetic ulcers

Diabetic foot ulcers are a major complication of diabetes that occurs following minor trauma. Diabetes-induced hyperglycemia is a leading factor inducing ulcer formation and manifests notably through the accumulation of advanced glycation end-products (AGEs) such as N-carboxymethyl-lysin. AGEs have a negative impact on angiogenesis, innervation, and reepithelialization causing minor wounds to evolve into chronic ulcers which increases the risks of lower limb amputation. However, the impact of AGEs on wound healing is difficult to model (both in vitro on cells, and in vivo in animals) because it involves a long-term toxic effect. We have developed a tissue-engineered wound healing model made of human keratinocytes, fibroblasts, and endothelial cells cultured in a collagen sponge biomaterial. To mimic the deleterious effects induced by glycation on skin wound healing, the model was treated with 300 µM of glyoxal for 15 days to promote AGEs formation. Glyoxal treatment induced carboxymethyl-lysin accumulation and delayed wound closure in the skin mimicking diabetic ulcers. Moreover, this effect was reversed by the addition of aminoguanidine, an inhibitor of AGEs formation. This in vitro diabetic wound healing model could be a great tool for the screening of new molecules to improve the treatment of diabetic ulcers by preventing glycation.     

Inhibition of miR‐21 alleviated cardiac perivascular fibrosis via repressing EndMT in T1DM

In type 1 and type 2 diabetes mellitus, increased cardiac fibrosis, stiffness and associated diastolic dysfunction may be the earliest pathological phenomena in diabetic cardiomyopathy. Endothelial‐mesenchymal transition (EndMT) in endothelia cells (ECs) is a critical cellular phenomenon that increases cardiac fibroblasts (CFs) and cardiac fibrosis in diabetic hearts. The purpose of this paper is to explore the molecular mechanism of miR‐21 regulating EndMT and cardiac perivascular fibrosis in diabetic cardiomyopathy. In vivo, hyperglycaemia up‐regulated the mRNA level of miR‐21, aggravated cardiac dysfunction and collagen deposition. The condition was recovered by inhibition of miR‐21 following with improving cardiac function and decreasing collagen deposition. miR‐21 inhibition decreased cardiac perivascular fibrosis by suppressing EndMT and up‐regulating SMAD7 whereas activating p‐SMAD2 and p‐SMAD3. In vitro, high glucose (HG) up‐regulated miR‐21 and induced EndMT in ECs, which was decreased by inhibition of miR‐21. A highly conserved binding site of NF‐κB located in miR‐21 5′‐UTR was identified. In ECs, SMAD7 is directly regulated by miR‐21. In conclusion, the pathway of NF‐κB/miR‐21/SMAD7 regulated the process of EndMT in T1DM, in diabetic cardiomyopathy, which may be regarded as a potential clinical therapeutic target for cardiac perivascular fibrosis.     

Adapter molecule DOC-2 is differentially expressed in pressure and volume overload hypertrophy and inhibits collagen synthesis in cardiac fibroblasts.

DOC-2 (differentially expressed in ovarian carcinoma) is involved in Ras-, beta-integrin-, PKC-, and transforming growth factor-beta-mediated cell signaling. These pathways are implicated in the accumulation of extracellular matrix proteins during progression of hypertrophy to heart failure; however, the role of DOC-2 in cardiac pathophysiology has never been examined. This study was undertaken to 1) analyze DOC-2 expression in primary cultures of cardiac fibroblasts and cardiac myocytes and in the heart following different types of hemodynamic overloads and 2) examine its role in growth factor-mediated ERK activation and collagen production. Pressure overload and volume overload were induced for 10 wk in Sprague-Dawley rats by aortic constriction and by aortocaval shunt, respectively. ANG II (0.3 mg.kg(-1).day(-1)) was infused for 2 wk. Results showed that, compared with myocytes, DOC-2 was found abundantly expressed in cardiac fibroblasts. Treatment of cardiac fibroblasts with ANG II and TPA resulted in increased expression of DOC-2. Overexpression of DOC-2 in cardiac fibroblasts led to inhibition of hypertrophy agonist-stimulated ERK activation and collagen expression. An inverse correlation between collagen and DOC-2 was observed in in vivo models of cardiac hypertrophy; in pressure overload and after ANG II infusion, increased collagen mRNA correlated with reduced DOC-2 levels, whereas in volume overload increased DOC-2 levels were accompanied by unchanged collagen mRNA. These data for the first time describe expression of DOC-2 in the heart and demonstrate its modulation by growth-promoting agents in cultured cardiac fibroblasts and in in vivo models of heart hypertrophy. Results suggest a role of DOC-2 in cardiac remodeling involving collagen expression during chronic hemodynamic overload.     

Biotin amelioration of nephrotoxicity in streptozotocin-induced diabetic mice

The current study was carried out to investigate the protective role of biotin in kidney injury and oxidative stress in diabetic mice type 1. Male Swiss albino mice were randomly divided into 3 groups. Control group received saline. Diabetes type 1 was induced in second and third groups by intraperitoneal injection of streptozotocin as a single dose (150 mg/kg). Second group remained as the untreated diabetic group and the third group received 15 mg/kg daily oral dose of biotin for 12 successive days. Biochemical results showed significant elevation in blood glucose and urea levels in both diabetic groups. Also, there is an increase in glomerular areas and decrease in glomerular cellularity in both diabetic groups. Histopathological results showed severe alterations in the untreated diabetic group represented by distorted glomeruli, inflammatory cells, and giant macrophages. In addition, there was an intense immune-reaction response toward acrolein indicator of oxidative damage. Upon biotin administration of diabetic mice, the above mentioned histopathological changes were reduced and also acroline reaction of oxidative damage was diminished. Our findings prove that biotin has a protective role against streptozotocin-induced oxidative damage in kidneys of laboratory mice.     

Cardiac overexpression of hormone-sensitive lipase inhibits myocardial steatosis and fibrosis in streptozotocin diabetic mice

Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL overexpression were generated, and cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased approximately 50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-alpha, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-beta, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, since HSL overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.