Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion (I/R) injury. We previously found the essential roles of endothelial nitric oxide synthase in the development of CR-induced cardioprotection and Sirt1 activation during CR (Shinmura K, Tamaki K, Ito K, Yan X, Yamamoto T, Katsumata Y, Matsuhashi T, Sano M, Fukuda K, Suematsu M, Ishii I. Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 308: H894–H903, 2015). However, the exact mechanism by which Sirt1 in cardiomyocytes mediates the cardioprotective effect of CR remains undetermined. We subjected cardiomyocyte-specific Sirt1 knockout (CM- Sirt1 −/− ) mice and the corresponding control mice to either 3-mo ad libitum feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia, followed by 60-min reperfusion. The recovery of left ventricle function after I/R was improved, and total lactate dehydrogenase release into the perfusate during reperfusion was attenuated in the control mice treated with CR, but a similar cardioprotective effect of CR was not observed in the CM- Sirt1 −/− mice. The expression levels of cardiac complement component 3 (C3) at baseline and the accumulation of C3 and its fragments in the ischemia-reperfused myocardium were attenuated by CR in the control mice, but not in the CM- Sirt1 −/− mice. Resveratrol treatment also attenuated the expression levels of C3 protein in cultured neonatal rat ventricular cardiomyocytes. Moreover, the degree of myocardial I/R injury in conventional C3 knockout ( C3 −/− ) mice treated with CR was similar to that in the ad libitum-fed C3 −/− mice, although the expression levels of Sirt1 were enhanced by CR. These results demonstrate that cardiac Sirt1 plays an essential role in CR-induced cardioprotection against I/R injury by suppressing cardiac C3 expression. This is the first report suggesting that cardiac Sirt1 regulates the local complement system during CR.
Macrophages regulate the inflammatory response and affect re-endothelialization. Inflammation and macrophages play important roles in promoting tissue repair, but p38α mitogen-activated protein kinase's role in re-endothelialization is unknown. Wire injuries of carotid arteries and Evans blue staining were performed in macrophage-specific p38α-knockout (p38αfl/flLysMCre+/-) mice and control mice (p38αfl/fl). Re-endothelialization of the carotid arteries at 3, 5 and 7 days was significantly promoted in p38αfl/flLysMCre+/- mice. In vitro experiments indicated that both the proliferation and migration of endothelial cells were enhanced in conditioned medium from peritoneal macrophages of p38αfl/flLysMCre+/- mice. Interleukin-6 (IL-6) level was decreased significantly in macrophages of p38αfl/flLysMCre+/- mice and an IL-6-neutralizing antibody promoted endothelial cell migration in vitro and re-endothelialization in p38αfl/fl mice in vivo. Phosphoproteomics revealed that the phosphorylation level of S544/T545/S549 sites in megakaryocytic leukemia 1 (MKL1) was decreased in p38αfl/flLysMCre+/- mice. The mutation of either S544/S549 or T545/S549 sites could reduce the expression of IL-6 and the inhibition of MKL1 reduced the expression of IL-6 in vitro and promoted re-endothelialization in vivo. p38α in macrophages aggravates injury of arteries by phosphorylating MKL1, and increasing IL-6 expression after vascular injury.
[Background] Adverse left ventricular (LV) remodeling after myocardial infarction (MI) is a major cause of heart failure. Myocardial necrosis releases or exposes normally sequestered antigenic cons...
Abstract Cardiovascular diseases originate from various pathogeneses, among which metabolic abnormalities are common. An integrated metabolic disturbance in common cardiovascular diseases has been suggested, particularly in the Asian population. This speculation is supported by the finding that aldehyde dehydrogenase 2 (ALDH2) gene mutations are present in nearly half of the Asian population. ALDH2 mutations significantly reduce ALDH2 enzyme activity and increase production of toxic aldehydes, including 4-hydroxynonenal, and are involved in the pathophysiology of several cardiovascular disorders such as atherosclerosis and myocardial infarction. Additionally, individuals with ALDH2 mutations are more susceptible to hypertension and diabetes, and these mutations are significantly correlated with heart failure. Until now there are no actionable clinical recommendations with regards to screening for ALDH2 mutations. A comprehensive understanding of the relationship between ALDH2 and these etiologies may greatly help in better prevention and treatment of cardiovascular diseases in populations, especially Asian, where ALDH2 mutations are common.
The B cell activating factor (BAFF) is a B cell survival factor involved in atherosclerosis and ischemia-reperfusion (IR) injury. This study sought to investigate whether BAFF is a potential predictor of poor outcomes in patients with ST-segment elevation myocardial infarction (STEMI).We prospectively enrolled 299 patients with STEMI, and serum levels of BAFF were measured. All subjects were followed for three years. The primary endpoint was major adverse cardiovascular events (MACEs), including cardiovascular death, nonfatal reinfarction, hospitalization for heart failure (HF), and stroke. Multivariable Cox proportional hazards models were constructed to analyze the predictive value of BAFF for MACEs.In multivariate analysis, BAFF was independently associated with risk of MACEs (adjusted HR 1.525, 95% CI 1.085-2.145; p = 0.015) and cardiovascular death (adjusted hazard ratio [HR] 3.632, 95% confidence interval [CI] 1.132-11.650, p = 0.030) after adjustment for traditional risk factors. Kaplan-Meier survival curves demonstrated that patients with BAFF levels above the cut-off value (1.46 ng/mL) were more likely to have MACEs (log-rank p < 0.0001) and cardiovascular death (log-rank p < 0.0001). In subgroup analysis, the impact of high BAFF on MACEs development was stronger in patients without dyslipidemia. Furthermore, the C-statistic and Integrated Discrimination Improvement (IDI) values for MACEs were improved with BAFF as an independent risk factor or when combined with cardiac troponin I.This study suggests that higher BAFF levels in the acute phase are an independent predictor of the incidence of MACEs in patients with STEMI.
Macrophages are involved in wound healing after myocardial infarction (MI). The role of Dectin-2, a pattern recognition receptor mainly expressed on myeloid cells, in the infarct healing remains unknown.The aim of this study is to determine whether Dectin-2 signaling is involved in the healing process and cardiac remodeling after MI and to elucidate the underlying molecular mechanisms.In a mouse model of permanent coronary ligation, Dectin-2, mainly expressed in macrophages, was shown to be increased in the early phase after MI. Dectin-2 knockout mice showed an improvement in the infarct healing and cardiac remodeling, compared with wild-type mice, which was demonstrated by significantly lower mortality because of cardiac rupture, increased wall thickness, and better cardiac function. Increased expression of α-smooth muscle actin and collagen I/III was observed, whereas the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 were decreased in the hearts of Dectin-2 knockout mice after MI. Dectin-2 deficiency inhibited the rate of apoptotic and necrotic cell death. However, Dectin-2 did not affect immune cell infiltration and macrophage polarization, but it led to a stronger activation of the Th1/interferon-γ immune reaction, through the enhancement of interleukin-12 production in the heart. Interferon-γ was shown to downregulate transforming growth factor-β-induced expression of α-smooth muscle actin and collagen I/III in isolated cardiac fibroblasts, leading to a decrease in migration and myofibroblast differentiation. Finally, Dectin-2 knockout improved myocardial ischemia-reperfusion injury and infarct healing.Dectin-2 leads to an increase in cardiac rupture, impairs wound healing, and aggravates cardiac remodeling after MI through the modulation of Th1 differentiation.
Background: Platelet endothelial cell adhesion molecule (PECAM-1) is present in the vascular endothelium and plays important roles in various biological processes. Several recent studies have reported associations between PECAM-1 and certain subtypes of cardiovascular diseases (CVDs). However, further research is necessary to clarify the causal effects of PECAM-1 on CVDs. To determine whether PECAM-1 and CVDs are causally associated, we conducted a two-sample Mendelian randomization (TSMR) study. Methods: Single nucleotide polymorphisms (SNPs) associated with PECAM-1 were used as instrumental variants (IVs) to estimate the causal effects of PECAM-1 on CVDs. Six SNPs were included in our TSMR study. The inverse-variance weighted (IVW) method was applied in the primary analysis. To confirm the initial results, we conducted several complementary analyses and pleiotropy analyses. Results: In the IVW analysis, higher genetically predicted PECAM-1 levels were associated with lower risk of coronary artery disease (CAD) (OR, 0.835; CI, 0.757–0.92; P = 3 × 10 −4 ) and myocardial infarction (MI) (OR, 0.79; CI, 0.709–0.881; P = 2.03 × 10 −5 ). Conclusions: The findings confirmed that elevated PECAM-1 levels may decrease the risk of CAD and MI. These results confirm the causal effect of PECAM-1 on CVDs and may facilitate further investigation of the mechanism of PECAM-1 in CVD pathogenesis.
Background: Several inflammatory factors have been demonstrated with diagnostic or prognostic value in patients with ischemic cardiomyopathy (ICM). Interleukin 34 (IL-34), an additional ligand of colony stimulating factor-1 receptor (CSF-1R), has been identified as a biomarker of coronary artery disease (CAD) and chronic kidney disease (CKD). However, the potential effect of IL-34 in ICM remains unknown. Methods: Serum IL-34 levels were detected in 360 subjects with ICM and in 465 subjects without ICM; the latter group included 233 controls without CAD and 232 patients with CAD and normal cardiac function. Uni- and multivariable logistic regression analyses were conducted to analyze the relationship between IL-34 and ICM. Results: IL-34 levels were significantly increased in patients with ICM compared with both groups of subjects without ICM (122.52 ± 115.30 vs. 95.02 ± 101.43 vs. 82.57 ± 84.24 pg/ml, respectively; P < 0.001). Moreover, serum IL-34 level was significantly positively correlated to NT-proBNP level (r = 0.223, P < 0.001), left ventricular end diastolic diameter and New York Heart Association (NYHA) functional class, indicating that a higher IL-34 level reflects more severe heart failure. Multivariable regression analyses revealed that IL-34 was remarkably associated with the presence and severity of ICM after adjusting for age, sex, conventional risk factors as well as medication (odds ratio (OR): 1.501, 95% confidence interval (CI): 1.249–1.803, P < 0.001, per SD increase). The predictive value of IL-34 value remained significant in patients already diagnosed with CAD. Conclusions: Increased IL-34 levels are relevant to the presence and severity of ischemic heart failure in all subjects and in patients with CAD. IL-34 may be used as a novel clinical biomarker of ICM with predictive value.
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