Potential adverse effects of coronavirus disease 2019 on the cardiovascular system.

Coronavirus disease 2019 (COVID-19) has spread, at an unprecedented speed and scale, into a global pandemic, infecting more than 29 million cases worldwide across 215 countries and territories and killing more than 930,000 individuals. There is evidence that preexisting cardiac disease can render individuals vulnerable. A large number of patients with COVID-19 present with preexisting cardiovascular disease or develop new-onset cardiac dysfunction during the course of the illness. Therefore, particular attention should be given to cardiovascular protection during COVID-19 treatment. This review highlights recent advances in our understanding of the interaction between COVID-19 and the cardiovascular system, with special attention to the virological, pathological, and immunological characteristics of COVID-19, acute myocardial injury, myocarditis, arrhythmias, coronary artery disease, heart function, and the possible mechanisms.

[Myocardial proliferation/regeneration in rats with experimental acute myocardial infarction].

OBJECTIVE: To investigate the myocardial proliferation/regeneration capacities at different time points and at different parts of the heart post acute myocardial infarction (AMI) in rats. METHODS: A total of 64 adult Sprague-Dawley (SD) rats were randomly divided into AMI group (left anterior descending coronary ligation, n = 44) and sham-operated group (n = 20). Rats were sacrificed on day 3, 5, 7, 14 and 60 respectively post operation (n = 5-9 at each time point) and ventricular tissues were harvested. 5-Bromo-2-deoxyUridine (Brdu, 50 mg/kg) was injected intraperitoneally at 12 and 24 hours before sacrifice. Morphological and pathological changes of the myocardium were observed after HE staining. Brdu-positive and c-kit and Brdu double-positive cardiomyocytes were analyzed post immunohistochemistry and immunofluorescence staining. Striated structure of new cells was detected by PTAH staining. Alpha-sarcomeric actin antibody was used to identify new cardiomyocytes. RESULT: Brdu-positive cardiomyocytes at border zone and non-ischemic zone were significantly increased at 5 days post AMI and peaked at 7th day post operation (Border zone, AMI: 1.26% ± 0.15% vs.Sham: 0.22% ± 0.06%, P < 0.01; right ventricle, AMI: 0.75% ± 0.12% vs.Sham: 0.18% ± 0.07%, P < 0.01). There was no significant difference between the two groups on the 60th post-operation day. Brdu-positive cells were 1.7-fold higher in infarct border zone than in the right ventricular area of AMI rats on the 7th post operation day (1.26% ± 0.15%, vs.0.75% ± 0.12%, P < 0.01) and was 1.4-fold higher on the 14th post operation day (0.77% ± 0.09%, vs.0.54% ± 0.11%, P < 0.01). PTAH staining evidenced myocardial striated structure inside the new cells. Immunofluorescent assay showed that parts of Brdu positive cells were myocardial actin positive, and the c-kit and Brdu double-positive myocardial cells were also observed. Most nuclei of tehse new cardiomyocytes were small and round-shaped. CONCLUSIONS: Myocardial proliferation/regeneration increased significantly after AMI in rats, especially around the infarct border zone. The myocardial proliferation/regeneration was time-dependent. Parts of the new cardiomyocytes had some characteristics of cardiac stem cells. This study suggests that myocardial proliferation/regeneration may be activated after acute myocardial injury.

PhiC31 integrase interacts with TTRAP and inhibits NFkappaB activation.

Phage PhiC31 integrase-mediated gene delivery is believed to be safer than using retroviral vectors since the protein confines its insertion of the target gene to a limited number of sites in mammalian genomes. To evaluate its safety in human cells, it is important to understand the interactions between this integrase and cellular proteins. Here we show that PhiC31 integrase interacts with TTRAP as presented by yeast two-hybrid and co-immunoprecipitation assays. Reducing the expression of endogenous TTRAP can increase the efficiency of PhiC31 integrase-mediated integration. A possible effect of interaction between PhiC31 integrase and TTRAP was highlighted by the fact that PhiC31 integrase inhibited the NFkappaB activation mediated by IL-1 in a dose-dependent manner. Because low dose of PhiC31 integrase can mediate considerable recombination events, we suggest that low dose of PhiC31 integrase be used when this integrase is applied in human cells.

TTRAP is a novel PML nuclear bodies-associated protein.

PML nuclear body (PML NB) is an important macromolecular nuclear structure that is involved in many essential aspects of cellular function. Tens of proteins have been found in PML NBs, and promyelocytic leukemia protein (PML) has been proven to be essential for the formation of this structure. Here, we showed that TRAF and TNF receptor-associated protein (TTRAP) was a novel PML NBs-associated protein. TTRAP colocalized with three important PML NBs-associated proteins, PML, DAXX and Sp100 in the typical fashion of PML NBs. By yeast mating assay, TTRAP was identified to interact with these PML NBs-associated proteins. The transcription and expression of TTRAP could be induced by IFN-gamma, representing another common feature of PML NBs-associated proteins. These results would not only be important for understanding PML NBs but also be helpful in studying the TTRAP function in the future.

Asymmetric dimethyl-arginine and coronary artery calcification in young adults entering middle age: the CARDIA Study.

BACKGROUND: Normal endothelial function depends on nitric oxide (NO) release by endothelial cells. Asymmetric dimethylarginine (ADMA), by competing with L-arginine, inhibits NO production and may lead to endothelial dysfunction and atherosclerotic development. Our aim was to ascertain the association between ADMA and coronary artery calcification (CAC), a marker of atherosclerotic coronary disease burden. DESIGN: A nested case-control study within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, an observational study among young adults residing in four US cities. METHODS: Participants were 263 white and black male and female cases with the presence of CAC and 263 sex and race-matched controls without evidence of CAC by computed tomography, 33-47 years old in 2000-2001. RESULTS: The median level (range) of ADMA was significantly higher in cases (0.55; 0.20-2.22 micromol/l) than in controls (0.53; 0.32-1.30 micromol/l; P=0.03). In conditional logistic regression adjusting for age, field center, educational attainment, smoking status, alcohol consumption, body mass index, waist circumference, hypertension, diabetes, low-density lipoprotein and high-density lipoprotein-cholesterol, triglycerides, renal function and C-reactive protein, the highest tertile of ADMA, compared with the lowest tertile, was associated with 1.80 (95% confidence interval 1.03-3.15) increased odds of the presence of any CAC. By linear regression, a significant independent relationship was also found between ADMA and the degree of CAC. CONCLUSION: These results support a role for ADMA as a biochemical marker of CAC.

A central role for nicotinic cholinergic regulation of growth factor-induced endothelial cell migration.

OBJECTIVE: An endothelial nicotinic acetylcholine receptor (nAChR) participates in atherogenesis and tumorigenesis by promoting neovascularization. To date, the mechanisms of nAChR-mediated angiogenesis and their relationship to angiogenic factors, eg, VEGF and bFGF, are unknown. METHODS AND RESULTS: Nicotine induced dose-dependent human microvascular endothelial cell (HMVEC) migration, a key angiogenesis event, to an extent which was equivalent in magnitude to bFGF (10 ng/mL) but less than for VEGF (10 ng/mL). Unexpectedly, nAChR antagonism not only abolished nicotine-induced HMVEC migration but also abolished migration induced by bFGF and attenuated migration induced by VEGF. Transcriptional profiling identified gene expression programs which were concordantly regulated by all 3 angiogens (nicotine, VEGF, and bFGF), a notable feature of which includes corepression of thioredoxin-interacting protein (TXNIP), endogenous inhibitor of the redox regulator thioredoxin. Furthermore, TXNIP repression by all 3 angiogens induced thioredoxin activity. Silencing thioredoxin by small interference RNA abrogated all angiogen-induced migration while silencing TXNIP strongly induced HMVEC migration. Interestingly, nAChR antagonism abrogates growth factor (VEGF and bFGF)-mediated induction of thioredoxin activity. CONCLUSIONS: Nicotine promotes angiogenesis via stimulation of nAChR-dependent endothelial cell migration. Furthermore, growth factor-induced HMVEC migration, a key angiogenesis event, requires nAChR activation--an effect mediated in part by nAChR-dependent regulation of thioredoxin activity.

Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence.

BACKGROUND: NO is a major regulator of cardiovascular physiology that reduces vascular and cardiac contractility. Accumulating evidence indicates that endogenous inhibitors may regulate NOS. The NOS inhibitors asymmetric dimethylarginine (ADMA) and N-monomethylarginine are metabolized by the enzyme dimethylarginine dimethylaminohydrolase (DDAH). This study was designed to determine if increased expression of DDAH could reduce tissue and plasma levels of the NOS inhibitors and thereby increase NO synthesis. METHODS AND RESULTS: We used gene transfer and transgenic approaches to overexpress human DDAH I in vitro and in vivo. The overexpression of DDAH in cultured endothelial cells in vitro induced a 2-fold increase in NOS activity and NO production. In the hDDAH-1 transgenic mice, we observed approximately 2-fold increases in tissue NOS activity and urinary nitrogen oxides, associated with a 2-fold reduction in plasma ADMA. The systolic blood pressure of transgenic mice was 13 mm Hg lower than that of wild-type controls (P<0.05). The systemic vascular resistance and cardiac contractility were decreased in response to the increase in NO production. CONCLUSIONS: DDAH I overexpression increases NOS activity in vitro and in vivo. The hDDAH-1 transgenic animal exhibits a reduced systolic blood pressure, systemic vascular resistance, and cardiac stroke volume. This study provides compelling evidence that the elaboration and metabolism of endogenous ADMA plays an important role in regulation of NOS activity.

Effect of urinary tract infection on ureteropelvic junction obstruction in a rat model.

OBJECTIVES: When a partially obstructed kidney becomes infected, more rapid and extreme renal parenchymal damage appears to occur than might result from either infection or obstruction alone. Previously, we showed that either bacteriuria or partial obstruction in congenital unilateral hydronephrosis causes elevated renal pelvic pressures in a rat model. In this same model, we examined the combined effects of partial upper tract obstruction and bacteriuria on renal pelvic and bladder pressures. METHODS: Female rats from an inbred colony in which more than one half are born with unilateral obstructive hydronephrosis were studied. Type 1 piliated Escherichia coli was instilled into the bladder. Two to 6 days later, the bladder and renal pelvic pressures were measured during varying urinary flows (less than 2 to more than 30 mL/kg/hr). All animals were killed and the kidneys and bladder grossly and histologically assessed. Hydronephrosis was determined at pathologic examination. RESULTS: Eight rats had congenital unilateral hydronephrosis; five were normal. Acute inflammation was found in all bladder and renal specimens. In hydronephrotic, infected kidneys, the renal pelvic pressures exceeded those in nonhydronephrotic, infected kidneys at all urinary flow rates. Bladder capacity and pressures did not differ between the two groups. CONCLUSIONS: This model demonstrates that the combination of infection and obstructive hydronephrosis in this model causes renal pelvic pressure elevation that is higher than that associated with either infection or obstructive hydronephrosis alone. These data demonstrate the compound effect that infection and obstruction may have on the kidney and offers an explanation for why this clinical situation is more likely to be associated with greater renal parenchymal injury than either alone.