This study reports the longest median survival to date (96 days) of pig hearts transplanted heterotopically into baboons. Duplication of these results in the orthotopic life-supporting position could bring cardiac xenotransplantation to the threshold of clinical application.
Background-Experience with non-antigenic galactose α1,3 galactose (αGal) polymers and development of αGal deficient pigs has reduced or eliminated the significance of this antigen in xenograft rejection. Despite these advances, delayed xenograft rejection (DXR) continues to occur most likely due to antibody responses to non-Gal endothelial cell (EC) antigens.
N a-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contractions via intracellular Cl − accumulation, membrane depolarization, and activation of voltage-gated Ca channels, leading to elevation of peripheral resistance.1 Indeed, NKCC1 knockout mice showed lower blood pressure because of decreased vascular tonus only when mice were fed a low-salt diet, as compared with those fed a normal diet, although dietary salt intake does not affect blood pressure in wild-type mice.2 This indicates that NKCC1 plays a key role in the regulation of myogenic tone in arteries by dietary salt intake.Pseudohypoaldosteronism type II is an autosomal-dominant disease characterized by salt-sensitive hypertension, hyperkalemia, and metabolic acidosis. 3 Mutations in with-no-lysine kinase 1 (WNK1) and WNK4 have been reported to cause pseudohypoaldosteronism type II. 4 It has been demonstrated previously that the WNK kinase family phosphorylated and activated oxidative stress-responsive kinase 1 (OSR1) and STE20/ SPS1-related proline/alanine-rich kinase (SPAK), and that these OSR1/SPAK kinases could phosphorylate and activate NKCC and Na-Cl cotransporter (NCC), which are solute carrier 12a (SLC12a) family cotransporters. This regulation of SLC12 family members by WNK-OSR1/SPAK signaling was confirmed in vivo in various genetically engineered mouse models. [5][6][7][8][9][10] Recently, the WNK-OSR1/SPAK-NKCC1 phosphorylation cascade in vascular smooth muscle cells was also found to be important for maintenance of vascular tone. Bergaya et al,8 as well as our group, 11 reported decreased NKCC1 phosphorylation in the aorta and decreased myogenic tone in the mesenteric arteries in WNK1 +/− mice, indicating that WNK1 plays Abstract-Na-K-Cl cotransporter isoform 1 (NKCC1) is involved in the regulation of vascular smooth muscle cell contraction. Recently, the with-no-lysine kinase (WNK)-STE20/SPS1-related proline/alanine-rich kinase (SPAK)-NKCC1 phosphorylation cascade in vascular smooth muscle cells was found to be important in the regulation of vascular tone. In this study, we investigated whether the WNK-SPAK-NKCC1 cascade in mouse aortic tissue is regulated by dietary salt intake and the mechanisms responsible. Phosphorylation of SPAK and NKCC1 was significantly reduced in the aorta in high-salt-fed mice and was increased in the aorta in low-salt-fed mice, indicating that the WNK-SPAK-NKCC1 phosphorylation cascade in the aorta was indeed regulated by dietary salt intake. Acute and chronic angiotensin II infusion increased phosphorylation of SPAK and NKCC1 in the mouse aorta. In addition, valsartan, an antagonist of angiotensin II type 1 receptor, inhibited low-salt diet-induced phosphorylation of SPAK and NKCC1, demonstrating that angiotensin II activates the WNK-SPAK-NKCC1 phosphorylation cascade through the angiotensin II type 1 receptor. However, a low-salt diet and angiotensin II together did not increase phosphorylation of SPAK and NKCC1 in the aorta in WNK3 knockout mice, indicating tha...
Significant prolongation in xenograft survival is achieved by improved immunosuppression. These results suggest that ongoing immune responses remain the major stimulus for DXR.
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