Anesthesia can affect respiratory, circulatory, and endocrine systems but is necessary for certain experimental procedures such as echocardiography and blood sampling in small animals. We have now investigated the effects of four types of anesthesia [pentobarbital sodium (PENT), ketamine-xylazine (K/X), and low- or high-dose isoflurane (ISO)] on hemodynamics, cardiac function, and glucose and lipid metabolism in Sprague-Dawley rats. Aortic pressure, heart rate, and echocardiographic parameters were measured at various time points up to 45 min after the induction of anesthesia, and blood was then collected for measurement of parameters of glucose and lipid metabolism. Systolic aortic pressure remained constant in the PENT group, whereas it showed a biphasic pattern in the K/X group and a gradual decline in the ISO groups. Marked bradycardia was observed in the K/X group. The serum glucose concentration was increased and the plasma insulin level was reduced in the K/X and ISO groups compared with the PENT group. The concentrations of free fatty acids and norepinephrine in plasma were increased in the K/X group. Despite the metabolic effects of K/X and ISO, our results suggest that the marked bradycardic effect of K-X renders this combination appropriate for measurement of Doppler-derived indexes of left ventricular diastolic function, whereas the relative ease with which the depth of anesthesia can be controlled with ISO makes it suitable for manipulations or data collection over long time periods. On the other hand, PENT may be best suited for experiments that focus on measurement of cardiac function by M-mode echocardiography and metabolic parameters.
Osteopontin (OPN) is involved in various physiological processes such as inflammatory and wound healing. However, little is known about the effects of OPN on these tissues. OPN is cleaved by thrombin, and cleavage of the N-terminal fragment exposes a SVVYGLR sequence on its C-terminus. In this study, we examined the effects of the thrombin-cleaved OPN fragments on fibroblasts and myocardial fibrosis, particularly the role of the SVVYGLR sequence. The recombinant thrombin-cleaved OPN fragments (N-terminal fragment [N-OPN], C-terminal fragment [C-OPN], and the N-terminal fragment lacking the SVVYGLR sequence [ΔSV N-OPN]) were added to fibroblasts, and the cellular motility, signal activity, and production of collagen were evaluated. A sustained-release gel containing an OPN fragment or SVVYGLR peptide was transplanted into a rat model of ischemic cardiomyopathy and the quantities and ratio of collagen type I (COL I) and type III (COL III) were estimated. N-OPN significantly promoted fibroblast migration. Smad signal activity, expression of smooth muscle actin (SMA), and the production of COL III were enhanced by N-OPN and SVVYGLR peptide. Conversely, ΔSV N-OPN and C-OPN had no effect. In vivo, the expression level of N-OPN was associated with COL III distribution, and the COL III/COL I ratio was significantly increased by the sustained-release gel containing N-OPN or SVVYGLR peptide. The cardiac function was also significantly improved by the N-OPN- or SVVYGLR peptide-released gel treatment. The N-terminal fragment of thrombin-cleaved OPN-induced Smad signal activation, SMA expression, and COL III production, and its SVVYGLR sequence influences this function.
Matrix metalloproteinases (MMPs) and a family of tissue inhibitors of metalloproteinases (TIMPs) may contribute to myocardial remodeling in heart failure. TIMPs are the main inhibitors of MMPs and have other MMP-independent functions. Because little is known of the role of TIMPs in the heart, we examined the effects of TIMPs on cardiac fibroblasts (CFs) and cardiomyocytes. In vitro, TIMP-1-4 enhanced smooth muscle actin (SMA) expression in CFs, and TIMP-1 and TIMP-3 enhanced the expression of phosphorylated Smad-3 and phosphorylated transforming growth factor (TGF)-β type 1 receptor in CFs; this effect was inhibited by TGF-β receptor blocker SB-505124. TIMPs-1, -3, and -4 also inhibited the FAK, AKT, and ERK pathways that induce cardiac hypertrophy. TIMP-1 and TIMP-2 suppressed apoptosis in cardiomyocytes; in contrast, TIMP-4 induced apoptosis in CFs. TIMP-2 stimulated collagen synthesis. Collagen gels containing TIMP-1 or TIMP-3, which exhibit cardioprotective effects in vitro, were transplanted to the left ventricular anterior wall of a rat heart model of myocardial infarction. Gel-released TIMP-1 and TIMP-3 significantly improved cardiac function and myocardial remodeling and enhanced SMA expression in the infarcted area in ischemic cardiomyopathy model rats. Further, the transplantation of TIMP-1 or TIMP-3 gels inhibited apoptosis in the ischemic myocardium and reduced MMP-2 activity. TIMPs may be an ideal target of cardiac regeneration therapy.
The effects of heat-killed Lactobacillus plantarum L-137 (HK L-137) on chronic inflammation associated with metabolic disorders have remained unknown. We examined the effects of HK L-137 on cardiac and adipose tissue pathophysiology in DahlS.Z-Leprfa/Leprfa (DS/obese) rats as a model of metabolic syndrome. DS/obese rats were treated orally with HK L-137 (2 or 75 mg kg−1 day−1) from 9 to 13 weeks of age. HK L-137 attenuated left ventricular (LV) inflammation and fibrosis as well as adipocyte hypertrophy, inflammation, and up-regulation of sterol regulatory element–binding protein–1c (SREBP-1c) gene expression in visceral and subcutaneous adipose tissue, without affecting body weight gain or hypertension. The low dose of HK L-137 also ameliorated LV diastolic dysfunction, the increase in subcutaneous fat mass, and insulin resistance as well as attenuated the down-regulation of Akt phosphorylation in visceral and subcutaneous adipose tissue, and the elevation of the circulating interleukin-6 concentration. Furthermore, the proportion of regulatory T (Treg) cells among CD4+ T cells in the spleen was increased by HK L-137. These results suggest that the anti-inflammatory effects of HK L-137 on the heart and adipose tissue are related, at least partly, to suppression of systemic inflammation associated with an increase in splenic Treg cell.
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