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Graphical abstract Abstract Myocardial infarction (MI) leads to the loss of cardiomyocytes, left ventricle (LV) dilation, and cardiac dysfunction, eventually developing into heart failure. Most of the strategies for MI therapy require biomaterials that can support tissue regeneration. In this study, we hypothesized that the extracellular matrix (ECM)-derived collagen I hydrogel loaded with histone deacetylase 7 (HDAC7)-derived-phosphorylated 7-amino-acid peptide (7Ap) could restrain LV remodeling and improve cardiac function after MI. An MI model was established by ligation of the left anterior descending coronary artery (LAD) of C57/B6 mice. The 7Ap-loaded collagen I hydrogel was intramyocardially injected to the infarcted region of the LV wall of the heart. After local delivery, the 7Ap-collagen increased neo-microvessel formation, enhanced stem cell antigen-1 positive (Sca-1+) stem cell recruitment and differentiation, decreased cellular apoptosis, and promoted cardiomyocyte cycle progression. Furthermore, the 7Ap-collagen restricted the fibrosis of the LV wall, reduced the infarct wall thinning, and improved cardiac performance significantly at 2 weeks post-MI. These results highlight the promising implication of 7Ap-collagen as a novel candidate for MI therapy. Statement of Significance The mammalian myocardium has a limited regenerative capability following myocardial infarction (MI). MI leads to extensive loss of cardiomyocytes, thus culminating in adverse cardiac remodeling and congestive heart failure. In situ tissue regeneration through endogenous cell mobilization has great potential for tissue regeneration. A 7-amino-acid-peptide (7A) domain encoded by a short open-reading frame (sORF) of the HDAC7 gene. The phosphorylated from of 7A (7Ap) has been reported to promote in situ tissue repair via the mobilization and recruitment of endogenous stem cell antigen-1 positive (Sca-l+) stem cells. In this study, 7Ap was shown to improve H9C2 cell survival, in vitro. In vivo investigations in a mouse MI model demonstrated that intra-myocardial delivery of 7Ap-loaded collagen hydrogel promoted neovascularization, stimulated Sca-l+ stem cell recruitment and differentiation, reduced cardiomyocyte apoptosis and promoted cell cycle progression. As a result, treated infarcted hearts had increased wall thickness, had improved heart function and exhibited attenuation of adverse cardiac remodeling, observed for up to 2 weeks. Overall, these results highlighted the positive impact of implanting 7Ap-collagen as a novel constituent for MI repair. [ABSTRACT FROM AUTHOR]

Chlamydia pneumoniae ( C. pneumoniae ) infection plays a potential role in angiogenesis. However, it is still an enigma how C. pneumoniae is involved in this process. Therefore, we investigated the effect of C. pneumoniae infection on angiogenesis, and then explored the roles of IQGAP1-related signaling in C. pneumoniae infection-induced angiogenesis. C. pneumoniae infection significantly enhanced angiogenesis as assessed by the tube formation assay possibly by inducing vascular endothelial cell (VEC) migration in the wound healing and Transwell migration assays. Subsequently, immunoprecipitation, Western blot and tube formation assay results showed that the phosphorylation of both IQGAP1 and N-WASP was required for the angiogenesis induced by C. pneumoniae infection. Our co-immunoprecipitation study revealed that IQGAP1 physically associated with N-WASP after C. pneumoniae infection of VECs. Actin polymerization assay further showed that in C. pneumoniae- infected VECs, both IQGAP1 and N-WASP were recruited to filamentous actin, and shared some common compartments localized at the leading edge of lamellipodia, which was impaired after the depletion of IQGAP1 by using the small interference RNA. Moreover, the knockdown of IQGAP1 also significantly decreased N-WASP phosphorylation at Tyr256 induced by C. pneumoniae infection. We conclude that C. pneumoniae infection promotes VEC migration and angiogenesis presumably through the IQGAP1-related signaling pathway. [ABSTRACT FROM AUTHOR]

Highlights: [•] cGMP induces acute cardioprotection by inactivating GSK-3β through PKG. [•] cGMP may prevent cardiac hypertrophy and heart failure by negatively regulating Akt. [•] The effect of cGMP on Akt is not mediated through PKG but is attributable to upregulation of PP2A activity. [•] cGMP has dual beneficial role in cardiac cell survival. [Copyright &y& Elsevier]

The effects of propyl paraben, an antimicrobial preservative, on voltage-dependent sodium current and myocardial ischemia-reperfusion injury were investigated in isolated adult rat cardiomyocytes. Whole cell voltage-clamp recording showed that propyl paraben reversibly blocked the voltage-gated sodium channel both in concentration- and voltage-dependent manners. Propyl paraben (500 μM but not 100 μM) significantly shifted the steady-state inactivation of the sodium channel toward the hyperpolarizing direction at the V1/2 point. Consistent with the above result, the propidium iodide (PI) uptake test revealed that pretreatment with 500 μM but not 100 μM of propyl paraben significantly reduced cell death induced by 45 min of sustained ischemia followed by 15 h of reperfusion (42.37 ± 7.01% of cell viability in control and 71.05 ± 7.06% in the propyl paraben group), suggesting that propyl paraben can protect myocytes from ischemia-reperfusion injury. These results indicate a possible correlation between the inhibition of sodium current and cardioprotection against ischemia-reperfusion injury. [Copyright &y& Elsevier]

Alterations in zinc transporter expression in response to zinc loss protect cardiac cells from ischemia/reperfusion (I/R) injury. However, the underlying molecular mechanisms how cardiac cells sense zinc loss remains unclear. Here, we found that zinc deficiency induced ubiquitination and degradation of the protein inhibitor of activated STAT3 (PIAS3), which can alleviate myocardial I/R injury by activating STAT3 to promote the expression of ZIP family zinc transporter genes. The RING finger domain within PIAS3 is vital for PIAS3 degradation, as PIAS3-dRing (missing the RING domain) and PIAS3-Mut (zinc-binding site mutation) were resistant to degradation in the setting of zinc deficiency. Meanwhile, the RING finger domain within PIAS3 is critical for the inhibition of STAT3 activation. Moreover, PIAS3 knockdown increased cardiac Zn2+ levels and reduced myocardial infarction in mouse hearts subjected to I/R, whereas wild-type PIAS3 overexpression, but not PIAS3-Mut, reduced cardiac Zn2+ levels, and exacerbated myocardial infarction. These findings elucidate a unique mechanism of zinc sensing, showing that fast degradation of the zinc-binding regulatory protein PIAS3 during zinc deficiency can correct zinc dyshomeostasis and alleviate reperfusion injury. [Display omitted] • Zinc deficiency induces the activation of STAT3, which acts as a transcription factor to promote upregulation of ZIP family zinc transporter gene expression, thereby compensating for Zn2+ loss. • PIAS3 can sense intracellular Zn2+ deficiency through its ubiquitination-mediated degradation and regulate the activity of STAT3. • Ring finger domain plays a critical role in PIAS3's ubiquitination and degradation by releasing Zn2+ in response to Zn2+ deficiency. • Knockdown of PIAS3 protected mouse hearts from I/R injury, whereas overexpression of PIAS3 exacerbated injury. [ABSTRACT FROM AUTHOR]

While it is well known that adenosine receptor activation protects the heart from ischemia/reperfusion injury, the precise mitochondrial mechanism responsible for the action remains unknown. This study probed the mitochondrial events associated with the cardioprotective effect of 5′-(N-ethylcarboxamido) adenosine (NECA), an adenosine A 2 receptor agonist. Isolated rat hearts were subjected to 30 min ischemia followed by 10 min of reperfusion, whereas H9c2 cells experienced 20 min ischemia and 10 min reperfusion. NECA prevented mitochondrial structural damage, decreases in respiratory control ratio (RCR), and collapse of mitochondrial membrane potential (ΔΨm). Both the adenosine A 2A receptor antagonist SCH58261 and A 2B receptor antagonist MRS1706 inhibited the action of NECA. NECA reduced mitochondrial proteins carbonylation, H 2 O 2 , and superoxide generation at reperfusion, but did not change superoxide dismutase (SOD) activity. In support, the protective effects of NECA and Peg-SOD on ΔΨm upon reperfusion were additive, implying that NECA's protection is attributable to the reduced superoxide generation but not to the enhancement of the superoxide-scavenging capacity. NECA increased the mitochondrial Src tyrosine kinase activity and suppressed complex I activity at reperfusion in a Src-dependent manner. NECA also reduced mitochondrial superoxide through Src tyrosine kinase. Studies with liquid chromatography-mass spectrometer (LC-MS) identified Tyr118 of the NDUFV2 subunit of complex 1 as a likely site of the tyrosine phosphorylation. Furthermore, the complex I activity of cells transfected with the Y118F mutant was increased, suggesting that this site might be a negative regulator of complex I activity. In support, NECA failed to suppress complex I activity at reperfusion in cells transfected with the Y118F mutant of NDUFV2. In conclusion, NECA prevents mitochondrial oxidative stress by decreasing mitochondrial superoxide generation through inhibition of complex I via the mitochondrial Src tyrosine kinase. Phosphorylation of Tyr 118 residue in NDUFV2 subunit may account for the inhibitory effect of NECA on complex I. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to test if atrial natriuretic peptide (ANP) can prevent the mitochondrial permeability transition pore (mPTP) opening by inactivating glycogen synthase kinase 3β (GSK-3β). ANP prevented loss of mitochondrial membrane potential (ΔΨ m) caused by H2O2 in a dose-dependent manner. Similarly, cyclosporin A, an inhibitor of the mPTP opening, could also preserve ΔΨ m. ANP increased GSK-3β phosphorylation at Ser9, pointing to that ANP inactivates GSK-3β. ANP could not prevent the loss of ΔΨ m in cells transfected with the constitutively active GSK-3β (GSK-3β-S9A) mutant. The effects of ANP on GSK-3β phosphorylation and ΔΨ m were reversed by the selective PKG inhibitor KT5823 [2,3,9,10,11,12-hexahydro-10R-methoxy-2,9-dimethyl-1-oxo-9S,12R-epoxy-1H-diindolo[1,2,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid, methyl ester]. In support, PKG markedly enhanced GSK-3β phosphorylation. ANP-induced GSK-3β phosphorylation was also abolished by the PI3K inhibitor LY294002 [2-(4-morpholinyl-4H-1-benzopyran-4-one hydrochloride)] and ANP could not prevent H2O2-induced loss of ΔΨ m in the presence of LY294002. These data suggest that ANP modulates the mPTP opening by inactivating GSK-3β through PKG and PI3K. GSK-3β is a common downstream target of PKG and PI3K. Prevention of the mPTP opening may underlie the mechanism for ANP’s protection against reperfusion injury. [Copyright &y& Elsevier]