Timely coronary artery reperfusion is essential to prevent myocyte death following myocardial infarction. The act of restoring blood flow however, paradoxically reduces the beneficial effects of reperfusion. This phenomenon, termed myocardial reperfusion injury, refers to the injury of cardiac myocytes that were viable immediately before reperfusion. Recent studies have shown that the timing and hemodynamic sequence of events which govern reperfusion can help to minimize the severity of reperfusion injury. The term postconditioning describes a modified form of reperfusion that involves a series of flow interruptions which confer significant cardioprotection to the heart. This thesis investigates ischemic postconditioning and endothelial nitric oxide synthase (eNOS) phosphorylation as cardioprotective therapies against reperfusion injury. In the first half of this thesis, we test the hypothesis that phosphorylation of eNOS serves as a cardioprotection nodal point for ischemic postconditioning. We show that phosphorylation of eNOS increases enzyme activity and that its product, nitric oxide, plays a critical role in cardioprotection. A number of cardiac dysfunctions arise after reperfusion and we address the effects of postconditioning on infarct size and myocardial blood flow. The second half of this thesis introduces the use of magnetic relaxometry sensors to detect cardiac biomarkers. The ability to non-invasively measure infarct size in small animals would be helpful in studying models of myocardial ischemia-reperfusion injury. We investigate the use of implantable biosensors in vivo and show that the cumulative detection of cardiac biomarkers correlates with infarct severity. / Engineering and Applied Sciences

In pregnancy, the maternal cardiovascular and placental circulation undergoes structural and functional changes to accommodate the growing fetus, but the mechanisms involved are not fully understood. Nitric oxide (NO) increases in normal pregnancy and lack of NO has been implicated in pregnancy related complications, preeclampsia and fetal growth restriction. Thus, the objective of the thesis was to determine if cardiovascular, uteroplacental and fetoplacental changes observed in human pregnancy also occur in mice and to assess the obligatory role of eNOS in mediating these changes. I showed that like humans, mice exhibit increases in maternal cardiac output, stroke volume, plasma volume, and uterine arterial blood flow, and a transient decrease in arterial pressure during pregnancy. Importantly, I showed that endothelial nitric oxide synthase (eNOS) plays an important role in promoting the progressive increase in maternal cardiac chamber dimensions and output and the enlargement of the aorta during pregnancy in mice. Another novel finding was that eNOS plays an important role in remodeling of the uterine and umbilical vasculatures during pregnancy. The remodeling of the uterine vasculatures, including the uterine and spiral arteries, were blunted in the eNOS KO mice with ko fetuses (KO(ko)) and this likely contributed to elevated vascular resistance and reduced perfusion of the uterine circulation during pregnancy. Impaired spiral artery remodeling may be caused by a deficiency in decidual uterine natural killer cells. Fetal placental vascularization was also impaired in eNOS KO(ko) mice, which likely increased vascular resistance and thereby reduced fetoplacental perfusion. Reduced vascularization may be due to decreased VEGF mRNA and protein expression in KO(ko) placentas. Decreased perfusion in both the uterine and umbilical circulations most likely contributed to elevated placental and fetal hypoxia in the eNOS KO(ko) mice. Interestingly, despite placental hypoxia, eNOS KO(ko) mice do not show the classical signs of preeclampsia including hypertension and proteinuria nor are maternal plasma sFlt1 levels elevated. Nevertheless, eNOS KO(ko) pups are growth restricted at term, and this is mainly due to the fetal genotype. These findings suggest that eNOS plays an essential role during pregnancy in remodeling of the maternal heart, aorta, and uterine and umbilical vasculatures thereby augmenting blood flow to the maternal and fetal sides of the placenta and thereby promoting fetal growth in mice.

In pregnancy, the maternal cardiovascular and placental circulation undergoes structural and functional changes to accommodate the growing fetus, but the mechanisms involved are not fully understood. Nitric oxide (NO) increases in normal pregnancy and lack of NO has been implicated in pregnancy related complications, preeclampsia and fetal growth restriction. Thus, the objective of the thesis was to determine if cardiovascular, uteroplacental and fetoplacental changes observed in human pregnancy also occur in mice and to assess the obligatory role of eNOS in mediating these changes. I showed that like humans, mice exhibit increases in maternal cardiac output, stroke volume, plasma volume, and uterine arterial blood flow, and a transient decrease in arterial pressure during pregnancy. Importantly, I showed that endothelial nitric oxide synthase (eNOS) plays an important role in promoting the progressive increase in maternal cardiac chamber dimensions and output and the enlargement of the aorta during pregnancy in mice. Another novel finding was that eNOS plays an important role in remodeling of the uterine and umbilical vasculatures during pregnancy. The remodeling of the uterine vasculatures, including the uterine and spiral arteries, were blunted in the eNOS KO mice with ko fetuses (KO(ko)) and this likely contributed to elevated vascular resistance and reduced perfusion of the uterine circulation during pregnancy. Impaired spiral artery remodeling may be caused by a deficiency in decidual uterine natural killer cells. Fetal placental vascularization was also impaired in eNOS KO(ko) mice, which likely increased vascular resistance and thereby reduced fetoplacental perfusion. Reduced vascularization may be due to decreased VEGF mRNA and protein expression in KO(ko) placentas. Decreased perfusion in both the uterine and umbilical circulations most likely contributed to elevated placental and fetal hypoxia in the eNOS KO(ko) mice. Interestingly, despite placental hypoxia, eNOS KO(ko) mice do not show the classical signs of preeclampsia including hypertension and proteinuria nor are maternal plasma sFlt1 levels elevated. Nevertheless, eNOS KO(ko) pups are growth restricted at term, and this is mainly due to the fetal genotype. These findings suggest that eNOS plays an essential role during pregnancy in remodeling of the maternal heart, aorta, and uterine and umbilical vasculatures thereby augmenting blood flow to the maternal and fetal sides of the placenta and thereby promoting fetal growth in mice.

Methylglyoxal (MG) is a reactive dicarbonyl metabolite formed during glucose, protein and fatty acid metabolism. In hyperglycemic conditions, an increased MG level has been linked to the development of diabetes and the accompanying vascular inflammation encountered at both macro- and microvascular levels. The present study explores the mechanisms of MG-induced leukocyte recruitment in mouse cremasteric microvasculature. Biochemical and intravital microscopy studies performed suggest that administration of MG (25 and 50 mg/kg) to mouse cremaster muscle tissue induces dose-dependent leukocyte recruitment in cremasteric vasculature with 84-92% recruited cells being neutrophils. MG treatment up-regulated the expression of endothelial cell (EC) adhesion molecules P-selectin, E-selectin and intercellular adhesion molecule-1 (ICAM-1) via the activation of nuclear factor-κB (NF-κB) signalling pathway and contributed to the increased leukocyte rolling flux, reduced leukocyte rolling velocity, and increased leukocyte adhesion, respectively. The inhibition of NF-κB blunted MG-induced endothelial adhesion molecule expression and thus attenuated leukocyte recruitment. Further study of signalling pathways revealed that MG induced Akt-regulated transient glycogen synthase kinase 3 (GSK3) activation in ECs, which was responsible for NF-κB activation at early time-points (< 1 h). After MG activation for 1 h, the endothelial GSK3 activity was decreased due to the up-regulation of serum- and glucocorticoid-regulated kinase 1 (SGK1), which was responsible for maintaining NF-κB activity at later time-points. Silencing GSK3 or SGK1 attenuated P-selectin, E-selectin and ICAM-1 expression in ECs, and abated MG-induced leukocyte recruitment. SGK1 also promoted cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) activity which was partially involved in ICAM-1 expression. Silencing CREB blunted ICAM-1 expression while P-selectin and E-selectin levels remained unaffected. MG also induced GSK3 activation in isolated neutrophils after 30 min treatment, an effect that was not responsible for MG-elicited Mac-1 expression. These data suggest the sequential activation of GSK3 and SGK1 in ECs as the pivotal signalling mechanism in MG-elicited leukocyte recruitment. Additionally, MG-treatment led to uncoupling of endothelial nitric oxide synthase (eNOS) following MG-induced superoxide generation in ECs. MG triggered eNOS uncoupling and hypophosphorylation associated with superoxide generation and biopterin depletion in EA.hy926 ECs. In cremaster muscle, as well as in cultured murine and human primary ECs, MG increased eNOS monomerization and decreased 5,6,7,8-tetrahydroboipterin (BH4)/total biopterin ratio, effects that were significantly mitigated by supplementation of BH4 or its precursor sepiapterin but not by NG-nitro-L-arginine methyl ester (L-NAME) or 5,6,7,8-tetrahydroneopterin (NH4). These observations confirm that MG administration triggers eNOS uncoupling. In murine cremaster muscle, MG triggered the reduction of leukocyte rolling velocity and the increases in rolling flux, adhesion, emigration and microvascular permeability. MG-induced leukocyte recruitment was significantly attenuated by supplementation of BH4 or sepiapterin or suppression of superoxide by L-NAME confirming the role of eNOS uncoupling in MG-elicited leukocyte recruitment. MG treatment further decreased the expression of guanosine triphosphate cyclohydrolase I in murine primary ECs, suggesting the impaired BH4 biosynthesis caused by MG. Taken together, these data suggest that vascular inflammation and endothelial dysfunction occurring in diabetes may be linked to GSK3/SGK1 regulated adhesion molecule expression, as well as the uncoupling of eNOS evoked by elevated levels of MG. These findings not only provide a better understanding of the role of MG in the development of diabetic vascular inflammation, but also suggest the potential therapeutic targets for MG-sensitive endothelial dysfunction in diabetes.

<p>RAS is a small GTPase that helps to convert extracellular cues into intracellular actions. It is the most commonly mutated oncogene and is found in an active mutant form in 90% of pancreatic cancers. Therefore, study of how this protein is made and then how this protein signals in the cell could provide the foundation for novel approaches to treat RAS-driven malignancies.</p><p>First I demonstrate that the level of protein expressed from the gene KRAS, but not the highly homologous gene HRAS, is limited in mammalian cells by an abundance of underrepresented (rare) codons in the encoding mRNA. KRAS mRNA from both ectopic plasmids as well as from the endogenous cellular gene is subject to slowed translation due to these rare codons within its coding sequence. This has consequences for tumorigenesis, as replacement of the rare codons with commonly used codons accelerates RAS driven tumor growth. This may extend beyond HRAS and KRAS, as many other homologous gene pairs show a high divergence in codon usage and protein expression, suggesting that this could be a wider phenomenon used by mammalian cells to regulate protein levels.</p><p>Second, I demonstrate that RAS driven tumors partially depend on eNOS for growth. Using genetically engineered mouse models that recapitulate the spontaneous development of pancreatic cancer, I demonstrate that the protein eNOS is progressively upregulated as tumors develop. I then demonstrate that genetic ablation of eNOS partially blocks the development of preinvasive pancreatic lesions in these mice, and trends toward increasing survival in mice that develop lethal pancreatic adenocarcinoma. Furthermore, I then show that inhibition of eNOS using the clinically tested small molecule L-NAME can also slow the development of preinvasive neoplasia and nonsignificantly increase survival, although not to the level of eNOS genetic ablation. These findings are applicable to a clinical setting, as in conjunction with others I show that L-NAME treatment of human pancreatic cancer xenografts halves their growth, even when the main side effect of L-NAME, hypertension, is treated.</p><p>Together, these studies provide a better understanding of how RAS functions within the cell, and thus, ultimately, how RAS driven cancers may be treated.</p> / Dissertation

Submitted by Lucienne Costa (lucienneferreira@ufcg.edu.br) on 2018-08-13T17:25:26Z No. of bitstreams: 1 JORDANNA SOUSA DE MELO – DISSERTAÇÃO (PPGMET) 2017.pdf: 3551837 bytes, checksum: 84c4d559fd24d6944745d0099094fe06 (MD5) / Made available in DSpace on 2018-08-13T17:25:26Z (GMT). No. of bitstreams: 1 JORDANNA SOUSA DE MELO – DISSERTAÇÃO (PPGMET) 2017.pdf: 3551837 bytes, checksum: 84c4d559fd24d6944745d0099094fe06 (MD5) Previous issue date: 2017-12-15 / Com o intuito de identificar e analisar as ondas de calor e de frio que ocorrem no Rio Grande do Sul foi utilizado quatro diferentes procedimentos em 13 estações meteorológicas, espacialmente distribuídas no Estado, entre os anos de 1961 a 2010. Foram consideradas ondas de calor e frio os períodos de cinco ou mais dias consecutivos de anomalias positivas e negativas de temperaturas máximas e mínimas, respectivamente. Calculou-se as médias climatológicas de temperaturas máximas e mínimas anual, estacional e diárias, e em seguida o número de ondas de calor e de frio para cada localidade, anual e sazonal pelos métodos Índice da Organização Meteorológica Mundial (IOMM), Índice Diário (ID), Índice Sazonal (IS) e RClimdex. Ao comparar os métodos verificou-se que o IOMM foi o que detectou o maior número de eventos, os métodos ID e IS praticamente não detectam ondas de calor no verão e de frio no inverno e o RClimdex mostrou-se incapaz de detectar a variabilidade internual de ondas de calor e frio no Rio Grande do Sul. Com relação às configurações espaciais das médias climatológicas das temperaturas do ar máximas e mínimas durante os dias de ondas de calor e frio, respectivamente, assim como os próprios números de dias de ondas calor e frio observou-se um gradiente do litoral para o interior e de sudeste para noroeste. De certa forma estas configurações é uma resposta aos efeitos da continentalidade, latitude e relevo. Quanto à associação da influencia dos eventos El Niño e La Niña no número de ondas de calor e frio observou-se que, em média, ocorrem um número maior de ondas de calor nos anos de El Niño e de frio nos anos de La Niña, entretanto, esta relação não é estatisticamente significativa. Portanto, não é possível afirmar categoricamente que em anos de El Niño tem-se um maior número de ondas de calor e nos de La Niña de frio. / In order to identify and analyze the heat and cold waves that occur in Rio Grande do Sul four different procedures were used in 13 meteorological stations, spatially distributed in the State, between 1961 and 2010. Heat waves were considered and periods of five or more consecutive days of positive and negative anomalies of maximum and minimum temperatures, respectively. The annual, seasonal and daily maximum and minimum climatic averages were calculated, followed by the number of heat and cold waves for each locality, annual and seasonal, using the World Meteorological Organization (IOMM), Daily Index (ID), Seasonal Index (IS) and RClimdex. When comparing the methods it was verified that the IOMM was the one that detected the greatest number of events, the ID and IS methods practically did not detect heat waves in summer and cold in the winter and RClimdex was unable to detect the internal variability of heat and cold waves in Rio Grande do Sul. Regarding the spatial configurations of the climatological means of the maximum and minimum air temperatures during the days of heat and cold waves, respectively, as well as the number of days of heat waves and cold it was observed a gradient of the coast inland and from southeast to northwest. In some ways these settings are a response to the effects of continental, latitude and relief. As for the association of the influence of the El Niño and La Niña events on the number of heat and cold waves, it was observed that, on average, a larger number of heat waves occur in the El Niño and cold years in La Niña, however, this relationship is not statistically significant. Therefore, it is not possible to state categorically that in El Niño years there is a greater number of heat waves and that of La Niña of cold.

Submitted by SIMONE REGINA POTJE null (simonepotje@hotmail.com) on 2017-01-20T14:12:22Z No. of bitstreams: 1 Tese Final Potje et al., 2017.pdf: 2363609 bytes, checksum: 76652ad37a98422f380b06f5e4c841b9 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-01-24T18:03:20Z (GMT) No. of bitstreams: 1 potje_sr_dr_araca.pdf: 2363609 bytes, checksum: 76652ad37a98422f380b06f5e4c841b9 (MD5) / Made available in DSpace on 2017-01-24T18:03:20Z (GMT). No. of bitstreams: 1 potje_sr_dr_araca.pdf: 2363609 bytes, checksum: 76652ad37a98422f380b06f5e4c841b9 (MD5) Previous issue date: 2016-12-16 / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) / O TERPY promove efeito hipotensor de maior magnitude em ratos hipertensos (SHR e 2R-1C) do que em ratos normotensos (Wistar e 2R). Foi demonstrado anteriormente que o endotélio prejudica o efeito vasodilatador do TERPY em aorta de Wistar. No entanto, observamos que o endotélio melhora os efeitos vasodilatadores do TERPY em aorta de SHR. Vasos sanguíneos de menor calibre, tais como as artérias de resistência, estão associadas ao controle da resitência vascular periférica e da pressão arterial. Nossa hipótese é que o TERPY induz relaxamento nas artérias mesentéricas de resistência em SHR e que as células endoteliais modulam positivamente o efeito do TERPY nestes vasos sanguíneos. Portanto, o nosso objetivo foi avaliar o efeito vasodilatador do TERPY em anéis com e sem endotélio de artéria mesentérica de ratos SHR, o seu mecanismo de relaxamento e a participação da NOS sobre esse efeito. e a Nossos resultados mostraram que o TERPY induziu um efeito vasodilatador dependente da concentração em anéis de artérias mesentéricas (2º e 3º ramos) de SHR e de ratos Wistar. A potência do TERPY foi maior em anéis intactos do que em anéis sem endotélio em artérias mesentéricas de SHR, mas em Wistar o endotélio prejudicou o efeito do TERPY. Nas artérias mesentéricas sem endotélio de SHR, o efeito do TERPY é dependente da atividade da guanilato ciclase solúvel e de canais para potássio. Nas artérias mesentéricas intactas de SHR, o efeito de TERPY depende da atividade de eNOS, mas não é dependente das atividades de nNOS, iNOS ou da via da ciclooxigenase. O TERPY promove a fosforilação da eNOS nos resíduos de serina1177 e aumenta a concentração de óxido nítrico em células endoteliais isoladas de artérias mesentéricas de SHR. Nossos resultados mostraram que a guanilato ciclase solúvel, os canais para potássio e a eNOS estão envolvidos no efeito vasodilatador estimulado pelo TERPY nas artérias de resistência mesentérica de SHR. Numa segunda parte deste estudo, avaliamos o mecanismo de ação de TERPY e seu efeito sobre a atividade da eNOS em células endoteliais. As células HUVEC, WT-HEK e HEK-eNOS foram tratadas com TERPY em diferentes tempos (0 a 60 minutos). Foram analisados por Western blotting o efeito do TERPY sobre a fosforilação de eNOS, monômero e dímero da eNOS e sobre monômero e oligômero de caveolina-1. Também foi avaliado o efeito do TERPY na interação eNOS/Cav-1 através de co-imunoprecipitação. As alterações induzidas pelo TERPY sobre as concentrações de espécies reativas de oxigênio e peroxinitrito em células endoteliais foram medidas usando sonda DHE e biossensor 7-CBA, respectivamente. A concentração de óxido nítrico (NO) foi avaliada por sonda DAF-FM e sensor Cooper. O TERPY promoveu desacoplamento e disfunção da eNOS, dependente de BH4. A desestabilização dos oligômeros da caveolina-1 foi induzida pelo TERPY. Consequentemente, o TERPY reduziu a interação eNOS/Cav-1 e promoveu ativação da eNOS. Nossos resultados mostraram que a atividade da eNOS pode ser regulada de duas maneiras diferentes pelo TERPY. O TERPY promove desacoplamento e fosforilação da eNOS, promovendo uma estratégia diferente para a regulação da atividade desta enzima. As moléculas químicas ou biológicas como o TERPY que regulam a atividade da eNOS e aumentam a produção e a biodisponibilidade de NO teriam ações terapêuticas importantes para o tratamento de doenças vasculares associadas a hipertensão. / CNPq: 141323/2013-2

abstract: According to the World Health Organization, obesity has nearly tripled since 1975 and forty-one million children under the age of 5 are overweight or obese (World Health Organization, 2018). Exercise is a potential intervention to prevent obesity-induced cardiovascular complications as exercise training has been shown to aid nitric oxide (NO) production as well as preserving endothelial function in obese mice (Silva et al., 2016). A soil-derived organic mineral compound (OMC) has been shown to lower blood sugar in diabetic mice (Deneau et al., 2011). Prior research has shown that, while OMC did not prevent high fat diet (HFD)-induced increases in body fat in male Sprague-Dawley rats, it was effective at preventing HFD-induced impaired vasodilation (M. S. Crawford et al., 2019). Six-weeks of HFD has been shown to impair vasodilation through oxidative-stress mediated scavenging of NO as well as upregulation of inflammatory pathways including inducible nitric oxide synthase (iNOS) and cyclooxygenase (Karen L. Sweazea et al., 2010). Therefore, the aim of the present study was to determine whether OMC alters protein expression of iNOS and endothelial NOS (eNOS) in the vasculature of rats fed a control or HFD with and without OMC supplementation. Six-week old male Sprague-Dawley rats were fed either a standard chow diet (CHOW) or a HFD composed of 60% kcal from fat for 10 weeks. The rats were administered OMC at doses of 0 mg/mL (control), 0.6 mg/mL, or 3.0 mg/mL added to their drinking water. Following euthanasia with sodium pentobarbital (200 mg/kg, i.p.), mesenteric arteries and the surrounding perivascular adipose tissue were isolated and prepared for Western Blot analyses. Mesenteric arteries from HFD rats had more uncoupled eNOS (p = 0.006) and iNOS protein expression (p = 0.027) than rats fed the control diet. OMC was not effective at preventing the uncoupling of eNOS or increase in iNOS induced by HFD. Perivascular adipose tissue (PVAT) showed no significant difference in iNOS protein expression between diet or OMC treatment groups. These findings suggest that OMC is not likely working through the iNOS or eNOS pathways to improve vasodilation in these rats, but rather, appears to be working through another mechanism. / Dissertation/Thesis / Masters Thesis Biology 2020

Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. Stroke is the leading cause of disability worldwide. HSPA12B, a heat-shock protein recently identified expression specifically in endothelial cells, is able to promote angiogenesis. Here, we have investigated its effects on functional recovery at chronic phase of ischaemic stroke. Ischaemic stroke was induced by 60 min. of middle cerebral artery occlusion in transgenic mice with overexpression of HSPA12B (HSPA12B Tg) and wild-type littermates (WT). HSPA12B Tg mice demonstrated a significant higher survival rate than WT mice within 28 days post-stroke. Significant improved neurological functions, increased spontaneous locomotor activity and decreased anxiety were detected inHSPA12B Tg mice compared with WT controls within 21 days post-stroke. Stroke-induced hippocampal degeneration was attenuated in HSPA12B Tg mice examined at day 28 post-stroke. Interestingly, HSPA12B Tg mice showed enhanced peri-infarct angiogenesis (examined 28 days post-stroke) and hippocampal neurogenesis (examined 7 days post-stroke), respectively, compared to WT mice. The stroke-induced eNOS phosphorylation and TGF-β1 expression were augmented in HSPA12B Tg mice. However, administration with eNOS inhibitor L-NAME diminished the HSPA12B-induced protection in neurological functional recovery and mice survival post-stroke. The data suggest that HSPA12B promoted functional recovery and survival after stroke in an eNOS-dependent mechanism. Targeting HSPA12B expression may have a therapeutic potential for the stroke-evoked functional disability and mortality.

AimsHSPA12B is a newly discovered and endothelial-cell-specifically expressed heat shock protein. We have reported recently that overexpression of HSPA12B increased endothelial nitric oxide synthase (eNOS) expression in mouse cardiac tissues during endotoxemia. Endothelial NOS has been shown to protect heart from ischaemic injury. We hypothesized that overexpression of HSPA12B will attenuate cardiac dysfunction and remodelling after myocardial infarction (MI) through an eNOS-dependant mechanism.Methods and resultsMI was induced by permanent ligation of the left anterior descending coronary artery in the transgenic mice (Tg) overexpressing hspa12b gene and its wild-type (WT) littermates. Echocardiographic analysis revealed that Tg mice exhibited improvements in cardiac dysfunction and remodelling at 1 and 4 weeks after MI. These improvements were accompanied by a significant decrease in cardiomyocyte apoptosis and increase in capillary and arteriolar densities. Significant up-regulation of eNOS, VEGF, Ang-1, and Bcl-2 was also observed in Tg hearts compared with WT hearts after MI. However, pharmacological inhibition of eNOS abolished the HSPA12B-induced decrease in cardiomyocyte apoptosis and increase in capillary formation after MI. Most importantly, inhibition of eNOS abrogated the protection of HSPA12B against cardiac dysfunction and remodelling after MI.ConclusionsThese data demonstrate for the first time that the overexpression of HSPA12B attenuates cardiac dysfunction and remodelling after MI. This action of HSPA12B was mediated, at least in part, by prevention of cardiomyocyte apoptosis and promotion of myocardial angiogenesis via an eNOS-dependent mechanism. HSPA12B could be a novel target for the management of patients with post-MI cardiac dysfunction and remodelling.