The recent discovery of the new components of the renin-angiotensin system (RAS) suggests the importance of the maintenance of cardiovascular structure and functions. To assess the role of the angiotensin-converting enzyme 2 (ACE2)-Mas receptor axis in the regulation of cardiac structure and function, the present work investigated the expression of ACE2 and Mas receptor in the heart in the cardiac remodeling that occurs in aortic constricted rats. Partial abdominal aortic ligation was carried out in Sprague-Dawley rats. Angiotensin AT1 receptor blockade and ACE inhibition were achieved by losartan and enalapril treatment, respectively. Results showed that aortic constriction increased left ventricular hypertrophy, fibrosis, mean arterial pressure (MAP), plasma renin activity (PRA) and cardiac ACE levels, but decreased the expression of cardiac ACE2 and Mas receptor. Losartan treatment significantly decreased MAP, left ventricle hypertrophy (LVH), fibrosis, and increased cardiac ACE2 and Mas expression. Enalapril also improved the cardiac parameters with a rise in cardiac ACE2, but did not change the Mas level. In conclusion, aortic constriction results in cardiac hypertrophy, fibrosis and a rise of cardiac ACE expression. Both AT1 receptor blocker and ACE inhibitor play a cardioprotective role in aortic constriction. However, AT1 receptor blocker particularly promotes cardiac ACE2 and Mas receptor levels. ACE inhibitor is associated with the inhibition of ACE and normalization of cardiac ACE2 activity.

The effects of enalapril and sodium depletion on renin synthesis and secretion were studied in mice with a left hydronephrotic kidney caused by unilateral ureteral ligation (UUL). In the control animals, there was no difference in plasma renin concentration between the right and left renal veins. In mice with left ureteral ligation, the renin concentration in the vein draining the hydronephrotic kidney was similar to or lower than that in the aorta under control conditions and after either stimulation with enalapril or depletion of sodium. Enalapril and sodium restriction increased plasma renin concentration, and this increase was due to secretion from the nonhydronephrotic kidney. The renin concentration per gram of kidney tissue and the mRNA for renin per gram of kidney tissue were similar in both the control and hydronephrotic kidney, and the values rose 3-4-fold in both kidneys after enalapril or sodium depletion. Immunostaining for renin confirmed these findings and indicated that renin per glomerulus was higher in the hydronephrotic kidney. Thus, removal or reduction of angiotensin II activity or depletion of sodium stimulated synthetic activity to a similar extent in the normal and hydronephrotic kidneys; however, secretion from the kidney without a macula densa (hydronephrotic) was not increased. Thus, the signals that control synthesis and secretion are different, and for these stimuli, secretion appears to require an intact macula densa.

We previously reported that sodium depletion increased renin secretion from the normal kidney in mice. We postulated that the combined procedures of sodium depletion and b-adrenoceptor blockade would affect the activity of the renin-angiotensin system. To test this hypothesis, we investigated the interaction of low sodium intake (LSI) and propranolol (PRO) on renin synthesis and secretion. To prevent the influence of tubule flow on renin secretion, mice with a left hydronephrotic kidney were used. LSI increased plasma renin concentration (PRC) 5.6-fold in the right renal vein (Po0.01). There was no net increase of PRC in the left renal vein. Tissue renin concentration (TRC) was elevated 3.6-fold and 1.3-fold in the right and left kidneys (Po0.01), respectively. After administration of PRO, PRC decreased by 34% in the right renal vein and 47% in the aorta (Po0.05); TRC was reduced by 37.5% in the right and 29.3% in the hydronephrotic kidneys (Po0.05). The combination of LSI and PRO increased PRC 3.4-fold and 1.8-fold in the right (Po0.01) and left renal veins (Po0.05), respectively. TRC increased 3.4-fold in the right (Po0.01) but only 61% in the left kidneys (Po0.05). The pattern in change of renin mRNA levels was similar to TRC but the absolute amount was smaller. There were correlations between PRC and renin mRNA, and between TRC and renin mRNA in both kidneys (Po0.001). Thus, LSI increased renin synthesis in both kidneys. However, there was no apparent renin secretion in the hydronephrotic kidney. PRO treatment suppressed renin synthesis and renin secretion, irrespective of hydronephrosis and LSI. The macula densa is critical for renin secretion under all of the circumstances studied.

Hydronephrosis increased cardiac ACE and suppressed ACE2 and Mas receptor levels. AT1 blockade caused sustained activation of cardiac ACE2 and Mas receptor, but ACE inhibitor had the limitation of such activation of Mas receptor in hydronephrotic animals.

Purpose: The aim of this study was to determine factors able to predict chemotherapeutic responses and clinical outcomes in patients with triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC). Methods: Fifty-two TNBC patients on taxane-anthracycline-based NAC were included. The expression of Ki67, topoisomerase IIα (TOPOIIα), and p53, as well as the presence of CD4+ tumor-infiltrating lymphocytes (TILs) and CD8+ TILs were evaluated in biopsy specimens by immunohistochemistry. The expression of Ki67, TOPOIIα, and p53, as well as CD4 and CD8 in TILs was calculated according to the pathological response to NAC, disease-free survival (DFS), and overall survival (OS). Results: Fourteen (26.9%) TNBC patients demonstrated a pathological complete response (pCR). According to univariate analyses, significant factors associated with pCR were high infiltration of CD4+ TILs (p = 0.004), high infiltration of CD8+ TILs (p = 0.010), and high expression of topoisomerase IIα (TOPOIIα) (p = 0.006). CD4+ TILs and TOPOIIα were significantly positively correlated with CD8+ TILs. Multivariate analyses indicated that TOPOIIα was an independent predictor of pCR. Although TNBC patients with high infiltration of CD4+ TILs, CD8+ TILs, or with high expression of TOPOIIα exhibited a significantly good 5-year DFS, only TNBC patients with a high infiltration of CD8+ TILs exhibited significantly positive 5-year OS probabilities. Conclusion: Our study demonstrated that CD4+ TILs and TOPOIIα in pretreated cancer tissues were significantly correlated with CD8+ TILs. CD4+ TILs, CD8+ TILs, and TOPOIIα expression were predictors of pCR and 5-year DFS of TNBC patients who were treated with NAC, and TOPOIIα was an independent predictor of pCR. CD8+ TILs were a key factor in the prediction of good 5-year OS rates of TNBC patients after taxane-anthracycline-based NAC.

The (pro)renin receptor [(P)RR] serves an important role in cardiovascular complications. However, the precise mechanisms of (P)RR in the heart remain obscure. The authors hypothesized that overexpression of (P)RR would be associated with activation of the relevant signal pathway which could lead to organ injury. The aim of the present study was to test the role of cardiac (P)RR and its potential signaling pathway components including phospholipase C (PLC), protein kinase C (PKC), extracellular signal-regulated kinase (ERK)1/2 and Raf-1 proto-oncogene, serine/threonine kinase (Raf-1). Hypertension and cardiac hypertrophy were induced by partial abdominal aortic ligation in Sprague-Dawley rats. The expression levels of cardiac (P)RR, PLC-β3, PKC, ERK1/2 and Raf-1 were measured following administration of the handle region peptide (HRP) and PLC-β3 inhibitor U73122. The expression of (P)RR and PLC-β3 significantly increased in the left ventricle (P<0.05). Levels of PKC-α, ERK1/2 and Raf-1 in the heart rose significantly (P<0.05). HRP and U73122 significantly decreased the levels of cardiac (P)RR and PLC-β3. Furthermore, levels of PKC-α, ERK1/2 and Raf-1 were also decreased (P<0.05). Cardiac parameters, blood pressure and plasma Angiotensin (Ang) I and Ang II levels were altered significantly (P<0.05). The results demonstrated that hypertension induced by aortic restriction activated the (P)RR in the heart. This action led to hypertension and cardiac hypertrophy via the (P)RR-PLC-β3-PKC-ERK1/2-Raf-1 signaling pathway. These results provide a mechanism by which elevated (P)RR levels in hypertension may contribute to the development of cardiac remodeling.

Background Recaticimab (SHR-1209, a humanized monoclonal antibody against PCSK9) showed robust LDL-C reduction in healthy volunteers. This study aimed to further assess the efficacy and safety of recaticimab in patients with hypercholesterolemia. Methods In this randomized, double-blind, placebo-controlled phase 1b/2 trial, patients receiving stable dose of atorvastatin with an LDL-C level of 2.6 mmol/L or higher were randomized in a ratio of 5:1 to subcutaneous injections of recaticimab or placebo at different doses and schedules. Patients were recruited in the order of 75 mg every 4 weeks (75Q4W), 150Q8W, 300Q12W, 150Q4W, 300Q8W, and 450Q12W. The primary endpoint was percentage change in LDL-C from the baseline to end of treatment (i.e., at week 16 for Q4W and Q8W schedule and at week 24 for Q12W schedule). Results A total of 91 patients were enrolled and received recaticimab and 19 received placebo. The dose of background atorvastatin in all 110 patients was 10 or 20 mg/day. The main baseline LDL-C ranged from 3.360 to 3.759 mmol/L. The least-squares mean percentage reductions in LDL-C from baseline to end of treatment relative to placebo for recaticimab groups at different doses and schedules ranged from −48.37 to −59.51%. No serious treatment-emergent adverse events (TEAEs) occurred. The most common TEAEs included upper respiratory tract infection, increased alanine aminotransferase, increased blood glucose, and increased gamma-glutamyltransferase. Conclusion Recaticimab as add-on to moderate-intensity statin therapy significantly and substantially reduced the LDL-C level with an infrequent administration schedule (even given once every 12 weeks), compared with placebo. Trial registration ClinicalTrials.gov, number NCT03944109

No abstract