Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype.

Project description:The Ca2+/calmodulin-dependent kinase II is expressed in smooth muscle and believed to mediate intracellular calcium handling and calcium-dependent gene transcription. CaMKII is activated by Angiotensin-II. The multifunctional calcium/calmodulin-dependent kinase II (CaMKII) is activated by Angiotensin-II (Ang-II) in vascular smooth muscle cells (VSMC), but its impact on hypertension remains unknown. In our transgenic mice that express the inhibitor peptide CaMKIIN in smooth muscle (TG SM-CaMKIIN), the blood pressure response to chronic Ang-II infusion was significantly reduced as compared to littermate controls. Surprisingly, examination of blood pressure and heart rate under ganglionic blockade revealed a key role for VSMC CaMKII in efferent sympathetic outflow in response to Ang II hypertension. Consistently, the efferent splanchnic nerve activity and plasma phenylephrine concentrations were significantly lower in TG SM-CaMKIIN mice as compared to littermates. Moreover, the aortic depressor nerve activity was reset in hypertensive wild type animals, but not in TG SM-CaMKIIN mice, suggesting that changes in baroreceptor wall activity may be responsible for the blood pressure difference in Ang-II hypertension. The pulse wave velocity, a measure of vascular wall stiffness in vivo, was increased in aortas of hypertensive compared to normotensive WT animals. However, Ang-II infusion did not alter the pulse wave velocity in transgenic mice, suggesting that CaMKII in VSMC controls structural smooth muscle genes. Accordingly, analysis of gene expression changes in aortas from wild type and TG SM-CaMKIIN hypertensive mice demonstrated that CaMKII inhibition mainly altered the expression of muscle contractile proteins. In contrast, TG SM-CaMKIIN aortas were protected from the Ang-II induced upregulation of genes linked to proliferation, suggesting that CaMKII inhibition prevents the Ang-II-induced reprogramming of smooth muscle cell gene expression towards a proliferative phenotype. 5 WT C57Bl/6 and 5 mice that express the Ca2+/calmodulin-dependent kinase II peptide inhibitor CaMKIIN in smooth muscle only (TG SM-CaMKIIN) were infused with 1.25 ug/kg/min Angiotensin-II by osmotic minipump for 14 days. 5 WT and 5 transgenic mice infused with normal saline served as controls. The mice were sacrificed on day 14 and the thoracic aortas isolated. RNA was isolated and pooled for the following groups: WT (wild type), C (TG SM-CaMKIIN), WT-A (WT with Angiotensin-II), C-A (TG SM-CaMKIIN + Angiotensin-II)

Project description:Background: The aim of this study is to improve our understanding of the mechanisms underlying the function of corticosteriods in the limb muscles of ICU patients with acute quadriplegic myopathy (AQM) by using a unique porcine ICU model, i.e., 5-day longitudinal experiments where animals are sedated, mechanically ventilated and exposed to factor triggering AQM that is hydrocortisone. Results: An increased expression of genes involved in kinase activity, cell cycle regulation and transcriptional regulation. A decreased expression in genes regulating heat shock proteins, cytoskeletal & sarcomeric and oxidative stress response were also apparent. Therefore, it appears that CS has an additive deleterious role in acute quadriplegic myopathywere also apparent. Conclusions: CS induced molecular mechanisms involving kinase activity and heat shock protein genes were forwarded as probable mechanisms underlying the decreased force generating capacity. Eight female domestic piglets (Sus scrofa, average body weight 26.4 kg) were used in this study. Piglets were immobilized by anesthesia and mechanically ventilated via a tracheotomy for a period of five days. During this study period, the animals were sedated using isoflurane inhalation (Abbott Laboratories, Chicago, Il, USA, 0.8 - 1.3% end-tidal concentration) supplemented by intravenous bolus doses of morphine and ketamine as needed. Core body temperature (blood) was maintained in the range of 38.5 - 40M-BM-0C by a servo controlled heating pad. The animals received intravenous crystalloid fluid (Ringeracetat) to maintain stable blood pressure and urinary output and a glucose infusion (Rehydrex, Fresenius Kabi, Stockholm, Sweden, 25 mg glucose /mL) in the range of 0.5 - 1.5 mg/kg/minute to decrease the effects of catabolism. Each animal received prophylactic streptomycin 750 mg/d and bensylpenicillin 600 mg/d (Streptocillin Vet, Boeringer-Ingelheim, Hellerup, Denmark). Arterial blood gas analysis as well as electrolytes and blood glucose levels were monitored regularly and kept in the normal range throughout the study period. A neuromuscular blocking agent (NMBA) was administered as a continuous infusion of pancuronium bromide 0.1mg/kg/h (Pavolun; Organon, Boxtel, The Netherlands) for 5days while a corticosteroid (CS) was given as bolus doses of hydrocortisone. Keywords: Treatment, immobilization, muscle function.

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Cardiovascular consequences of K(ATP) dysfunction in Cantu Syndrome arising from in mutations Kir6.1 (KCNJ8) and SUR2 (ABCC9)

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