Effects of Spironolactone on Hypoxia-Inducible Factor-1α in the Patients Receiving Coronary Artery Bypass Grafting.

ABSTRACT: We explored the protective effect of spironolactone on cardiac function in the patients undergoing coronary artery bypass grafting (CABG) by determining serum hypoxia-inducible factor-1α (HIF-1α) before and after CABG. We used the propensity score matching method retrospectively to select 174 patients undergoing CABG in our hospital from March 2018 to December 2019. Of the 174 patients, 87 patients taking spironolactone for more than 3 months before CABG were used as a test group and other 87 patients who were not taking spironolactone as a control group. In all patients, serum HIF-1α and troponin I levels were determined before as well as 24 hours and 7 days after CABG, serum N-terminal probrain natriuretic peptide (NT-proBNP) level was determined before as well as 12, 24, and 36 hours after CABG, and electrocardiographic monitoring was performed within 36 hours after CABG. The results indicated that there were no significant differences in the HIF-1α level between the test group and the control group before and 7 days after CABG, but the HIF-1α level was significantly lower in the test group than that in the control group 24 hours after CABG (P < 0.01). The 2 groups were not significantly different in the troponin I level at any time point. There was no significant difference in the serum NT-proBNP level between the test group and the control group before CABG, but NT-proBNP (BNP) levels were all significantly lower in the test group than those in the control group at postoperative 12, 24, and 36 hour time points (all P <0.05). The incidence of postoperative atrial fibrillation was also significantly lower in the test group than that in the control group (P = 0.035). Spironolactone protects cardiac function probably by improving myocardial hypoxia and inhibiting myocardial remodeling.

Cardiac ankyrin repeat protein attenuates cardiomyocyte apoptosis by upregulation of Bcl-2 expression.

Cardiac ankyrin repeat protein (CARP) is a nuclear transcriptional co-factor that has additional functions in the myoplasm as a component of the muscle sarcomere. Previous studies have demonstrated increased expression of CARP in cardiovascular diseases, however, its role in cardiomyocyte apoptosis is unclear and controversial. In the present study, we investigated possible roles of CARP in hypoxia/reoxygenation (H/R) -induced cardiomyocyte apoptosis and the underlying mechanisms. Neonatal mouse ventricular cardiomyocytes were isolated and infected with adenovirus encoding Flag-tagged CARP (Ad-CARP) and lentivirus encoding CARP targeted shRNA (sh-CARP), respectively. Cardiomyocyte apoptosis induced by exposure to H/R conditions was evaluated by TUNEL staining and western blot analysis of cleaved caspase-3. The results showed that H/R-induced apoptosis was significantly decreased in Ad-CARP cardiomyocytes and increased in sh-CARP cardiomyocytes, suggesting a protective anti-apoptosis role for CARP. Interestingly, over-expressed CARP was mainly distributed in the nucleus, consistent with its role in regulating transcriptional activity. qPCR analysis showed that Bcl-2 transcripts were significantly increased in Ad-CARP cardiomyocytes. ChIP and co-IP assays confirmed the binding of CARP to the Bcl-2 promoter through interaction with transcription factor GATA4. Collectively, our results suggest that CARP can protect against H/R induced cardiomyocyte apoptosis, possibly through increasing anti-apoptosis Bcl-2 gene expression.

SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction.

SIRT1 has been proved to rejuvenate and improve the therapeutic efficacy of aged rat mesenchymal stem cells (MSCs). Herein, we investigate the protective effect of pretreatment with SIRT1 activator SRT1720 on aged human MSCs (hMSCs). The optimized pretreatment condition for aged hMSCs was determined to be 0.5 µM SRT1720 for 24 h by monitoring the survival of aged hMSCs subjected to serum deprivation±hypoxia and±500 µM hydrogen peroxide (H2O2). Pretreatment with these conditions increased the survival of aged hMSCs 1 day (2.7-fold) and 3 days (1.9-fold) after being transplanted into a rat myocardial infarction (MI) model created by ligation of the left anterior descending (LAD) coronary artery. Transplantation with SRT1720 pretreated aged hMSCs achieved increased left ventricular ejection fraction (58.9±3.6 versus 52.8±5%) and angiogenesis with reduced fibrosis of rat hearts as compared to DMSO pretreated group 28 days following MI. Unbiased transcriptome analysis conducted on aged hMSCs under oxidative stress indicated the Fas apoptosis inhibitory molecule (FAIM) was significantly upregulated following SRT1720 pretreatment (14.9±0.2-folds). Moreover, the anti-apoptotic effect of SRT1720 was mitigated by FAIM knockdown with a small interfering RNA-targeted FAIM. These results indicated that pretreatment with SRT1720 improves survival of aged hMSCs, and enhances their therapeutic efficacy for rat myocardial infarction (MI). Upregulation of FAIM possibly involves in the mechanisms of the protective effects.

Roles of SIRT3 in heart failure: from bench to bedside.

Heart failure (HF) represents the most common endpoint of most cardiovascular diseases (CVDs) which are the leading causes of death around the world. Despite the advances in treating CVDs, the prevalence of HF continues to increase. It is believed that better results of prognosis are obtained from prevention rather than additional treatment for HF. Therefore, it is reasonable to prevent the development of CVDs or other complications to HF. Most types of HF are attributed to contractile dysfunction, cardiac hypertrophy or remodeling, and ischemic injuries. SIRT3 is a mitochondrial nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase whose substrates vary from metabolic biogenesis-associated proteins to stress-responsive proteins. In recent years, a number of studies have highlighted the cardio-protective role of SIRT3 and, as such, efforts have been made to induce over-expression or increased activity of this protein. In this review, we provide an overview of the roles of SIRT3 in cardiac hypertrophy induced by pressure overload or agonists and cardiomyocytes ischemic injuries. Moreover, we will introduce the application of SIRT3 agonists in the prevention of cardiac hypertrophy and ischemia reperfusion injury.

SIRT1 ameliorates age-related senescence of mesenchymal stem cells via modulating telomere shelterin.

Mesenchymal stem cells (MSCs) senescence is an age-related process that impairs the capacity for tissue repair and compromises the clinical use of autologous MSCs for tissue regeneration. Here, we describe the effects of SIRT1, a NAD(+)-dependent deacetylase, on age-related MSCs senescence. Knockdown of SIRT1 in young MSCs induced cellular senescence and inhibited cell proliferation whereas overexpression of SIRT1 in aged MSCs reversed the senescence phenotype and stimulated cell proliferation. These results suggest that SIRT1 plays a key role in modulating age-induced MSCs senescence. Aging-related proteins, P16 and P21 may be downstream effectors of the SIRT1-mediated anti-aging effects. SIRT1 protected MSCs from age-related DNA damage, induced telomerase reverse transcriptase (TERT) expression and enhanced telomerase activity but did not affect telomere length. SIRT1 positively regulated the expression of tripeptidyl peptidase 1 (TPP1), a component of the shelterin pathway that protects chromosome ends from DNA damage. Together, the results demonstrate that SIRT1 quenches age-related MSCs senescence by mechanisms that include enhanced TPP1 expression, increased telomerase activity and reduced DNA damage.

Transplantation of SIRT1-engineered aged mesenchymal stem cells improves cardiac function in a rat myocardial infarction model.

BACKGROUND: Previous studies have demonstrated that biological aging has a negative influence on the therapeutic effects of mesenchymal stem cells (MSCs)-based therapy. Using a rat myocardial infarction (MI) model, we tested the hypothesis that silent mating type information regulation 2 homolog 1 (SIRT1) may ameliorate the phenotype and improve the function of aged MSCs and thus enhance the efficacy of aged MSCs-based therapy. METHODS: Sixty female rats underwent left anterior descending coronary artery ligation and were randomly assigned to receiving: intramyocardial injection of cell culture medium (DMEM group); SIRT1 overexpression vector-treated aged MSCs (SIRT1-aged MSCs group) obtained from aged male SD rats or empty vector-treated aged MSCs (vector-aged MSCs group). Another 20 sham-operated rats that underwent open-chest surgery without coronary ligation or any other intervention served as controls. RESULTS: SIRT1-aged MSC group exhibited enhanced blood vessel density in the border zone of MI hearts, which was associated with reduced cardiac remodeling, leading to improved cardiac performance. Consistent with the in vivo data, our in vitro experiments also demonstrated that SIRT1 overexpression ameliorated aged MSCs senescent phenotype and recapitulated the pro-angiogenesis property of MSCs and conferred the anti-stress response capabilities, as indicated by increases in pro-angiogenic factors, angiopoietin 1 (Ang1) and basic fibroblast growth factor (bFGF), expressions and a decrease in anti-angiogenic factor thrombospondin-1 (TBS1) at mRNA levels, and increases in Bcl-2/Bax ratio at protein level. CONCLUSIONS: Up-regulating SIRT1 expression could enhance the efficacy of aged MSCs-based therapy for MI as it relates to the amelioration of senescent phenotype and hence improved biological function of aged MSCs.