Sodium overload during postnatal phases impairs diastolic function and exacerbates reperfusion arrhythmias in adult rats.

Sodium overload during childhood impairs baroreflex sensitivity and increases arterial blood pressure and heart rate in adulthood; these effects persist even after high-salt diet (HSD) withdrawal. However, the literature lacks details on the effects of HSD during postnatal phases on cardiac ischemia/reperfusion responses in adulthood. The current study aimed to elucidate the impact of HSD during infancy adolescence on isolated heart function and cardiac ischemia/reperfusion responses in adulthood. Male 21-day-old Wistar rats were treated for 60 days with hypertonic saline solution (NaCl; 0.3M; experimental group) or tap water (control group). Subsequently, both groups were maintained on a normal sodium diet for 30 days. Subsequently, the rats were euthanized, and their hearts were isolated and perfused according to the Langendorff technique. After 30 min of the basal period, the hearts were subjected to 20 min of anoxia, followed by 20 min of reperfusion. The basal contractile function was unaffected by HSD. However, HSD elevated the left ventricular end-diastolic pressure during reperfusion (23.1 ± 5.2 mmHg vs. 11.6 ± 1.4 mmHg; p < 0.05) and increased ectopic incidence period during reperfusion (208.8 ± 32.9s vs. 75.0 ± 7.8s; p < 0.05). In conclusion, sodium overload compromises cardiac function after reperfusion events, diminishes ventricular relaxation, and increases the severity of arrhythmias, suggesting a possible arrhythmogenic effect of HSD in the postnatal phases.

microRNA-449a reduces growth hormone-stimulated senescent cell burden through PI3K-mTOR signaling.

Cellular senescence, a hallmark of aging, has been implicated in the pathogenesis of many major age-related disorders, including neurodegeneration, atherosclerosis, and metabolic disease. Therefore, investigating novel methods to reduce or delay the accumulation of senescent cells during aging may attenuate age-related pathologies. microRNA-449a-5p (miR-449a) is a small, noncoding RNA down-regulated with age in normal mice but maintained in long-living growth hormone (GH)-deficient Ames Dwarf (df/df) mice. We found increased fibroadipogenic precursor cells, adipose-derived stem cells, and miR-449a levels in visceral adipose tissue of long-living df/df mice. Gene target analysis and our functional study with miR-449a-5p have revealed its potential as a serotherapeutic. Here, we test the hypothesis that miR-449a reduces cellular senescence by targeting senescence-associated genes induced in response to strong mitogenic signals and other damaging stimuli. We demonstrated that GH downregulates miR-449a expression and accelerates senescence while miR-449a upregulation using mimetics reduces senescence, primarily through targeted reduction of p16Ink4a, p21Cip1, and the PI3K-mTOR signaling pathway. Our results demonstrate that miR-449a is important in modulating key signaling pathways that control cellular senescence and the progression of age-related pathologies.

Angiotensin-(1-7) attenuates the negative inotropic response to acetylcholine in the heart.

Previous studies have suggested that the Angiotensin-(1-7) [(Ang-(1-7)] can change cardiac function by modulating the autonomic nervous system. However, it is unknown whether the Ang-(1-7) can modulate the effect of acetylcholine (ACh) in ventricular contractility. Thus, this study aimed to investigate whether Ang-(1-7) modifies the amplitude of the cardiac cholinergic effects and if these effects are intrinsic to the heart. In anesthetized Wistar rats, Ang-(1-7) attenuated the effect of ACh in decreasing the left ventricular end-systolic pressure (LVESP), dP/dtmax, and dP/dtmin, but did not modify the hypotensive effect of ACh. Similarly, Ang-(1-7) attenuated the reduction of the LVESP, dP/dtmax, and dP/dtmin evoked by ACh in isolated hearts. These effects were blocked by the Mas receptor antagonist, A-779, but not by the adenylyl cyclase inhibitor MDL-12,330 A. Ang-(1-7) also attenuated the reduction in the maximum contraction and relaxation speeds and the shortening promoted by ACh in isolated cardiomyocytes. These data show that Ang-(1-7) acting through Mas receptor counter-regulates the myocardial contractile response to ACh in an arterial pressure and heart rate-independent manner.

Cardioprotective effects of the proline-rich oligopeptide Bj-PRO-7a in spontaneously hypertensive rats.

The proline-rich oligopeptide from Bothrops jararaca snake venom, Bj-PRO-7a, promotes acute effects in blood pressure in hypertensive animals. However, the cardiac effects of this heptapeptide are completely unknown. Thus, we sought to evaluate whether the Bj-PRO-7a could protect against cardiac remodelling in spontaneously hypertensive rats (SHR). SHR were treated with Bj-PRO-7a (71 nmol/kg/day, s.c.) or saline for 28 days. Wistar rats were used as control. Systolic blood pressure (SBP) and heart rate (HR) were measured by tail-cuff plethysmography. Cardiomyocyte diameter and interstitial and perivascular fibrosis of the left ventricle (LV) were evaluated using Picrosirius staining. Immunofluorescence was used to detect collagen I and III. Fibroblast proliferation was assessed by immunohistochemistry to detect proliferating cell nuclear antigen (PCNA). Protein expression was assessed by western blot. The superoxide dismutase and catalase activities and the concentration of lipid peroxidation products were evaluated in the LV. The SBP and HR were not different between treated and non-treated SHR at the end of the treatment. However, Bj-PRO-7a attenuated the cardiomyocyte hypertrophy, deposition of interstitial and perivascular fibrosis and collagen I, and positive PCNA-labelled fibroblasts. This peptide also reduced the increased levels of TBARS, expression and activity of catalase, and activity of SOD in LV from SHR. Also, the Bj-PRO-7a increased the expression of metalloproteinases-2 in SHR hearts. These findings demonstrate that the Bj-PRO-7a reduced the pathological cardiac remodelling in a pressure-independent manner in hypertensive rats through mechanisms mediated by oxidative stress regulation.

Senolytic Combination of Dasatinib and Quercetin Alleviates Intestinal Senescence and Inflammation and Modulates the Gut Microbiome in Aged Mice.

Cellular senescence contributes to age-related disorders including physical dysfunction, disabilities, and mortality caused by tissue inflammation and damage. Senescent cells accumulate in multiple tissues with aging and at etiological sites of multiple chronic disorders. The senolytic drug combination, Dasatinib plus Quercetin (D+Q), is known to reduce senescent cell abundance in aged mice. However, the effects of long-term D+Q treatment on intestinal senescent cell and inflammatory burden and microbiome composition in aged mice remain unknown. Here, we examine the effect of D+Q on senescence (p16Ink4a and p21Cip1) and inflammation (Cxcl1, Il1ß, Il6, Mcp1, and Tnfα) markers in small (ileum) and large (caecum and colon) intestine in aged mice (n = 10) compared to age-matched placebo-treated mice (n = 10). Additionally, we examine microbial composition along the intestinal tract in these mice. D+Q-treated mice show significantly lower senescent cell (p16 and p21 expression) and inflammatory (Cxcl1, Il1ß, Il6, Mcp1, and Tnfα expression) burden in small and large intestine compared with control mice. Further, we find specific microbial signatures in ileal, cecal, colonic, and fecal regions that are distinctly modulated by D+Q, with modulation being most prominent in small intestine. Further analyses reveal specific correlation of senescence and inflammation markers with specific microbial signatures. Together, these data demonstrate that the senolytic treatment reduces intestinal senescence and inflammation while altering specific microbiota signatures and suggest that the optimized senolytic regimens might improve health via reducing intestinal senescence, inflammation, and microbial dysbiosis in older subjects.