Chronic hypertension alters the expression of Cx43 in cardiovascular muscle cells

Abstract

Connexin43 (Cx43), the predominant gap junction protein of muscle cells in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension on the expression of Cx43 in aorta and heart in three different models of experimental hypertension. Rats were made hypertensive either by clipping one renal artery (two kidney, one-clip renal (2K,1C) model) by administration of deoxycorticosterone and salt (DOCA-salt model) or by inhibiting nitric oxide synthase with N G -nitro-L-arginine methyl ester (L-NAME model). After 4 weeks, rats of the three models showed a similar increase in intra-arterial mean blood pressure and in the thickness of the walls of both aorta and heart. Analysis of heart mRNA demonstrated no change in Cx43 expression in the three models compared to their respective controls. The same 2K,1C and DOCAsalt hypertensive animals expressed twice more Cx43 in aorta, and the 2K,1C rats showed an increase in arterial distensibility. In contrast, the aortae of L-NAME hypertensive rats were characterized by a 50% decrease in Cx43 and the carotid arteries did not show increased distensibility. Western blot analysis indicated that Cx43 was more phosphorylated in the aortae of 2K,1C rats than in those of L-NAME or control rats, indicating a differential regulation of aortic Cx43 in different models of hypertension. The data suggest that localized mechanical forces induced by hypertension affect Cx43 expression and that the cell-to-cell communication mediated by Cx43 channels may contribute to regulating the elasticity of the vascular wall. Correspondence

Vascular Gap Junctions in Hypertension

“…Cx40 and Cx37 were found to be reduced in ECs and VSMCs, 39,[53][54][55] and both increases and decreases in Cx43 have been reported. 39,55 In ECs isolated from mesenteric arteries of SHRs, Goto et al 56 found no change in either Cx40 or Cx43 but a decrease in Cx37.…”

“…52 Yeh et al 52 found that hypertension-associated expression of ECs Cx43 and Cx37 was largely reversed in N w -nitro-L-arginine methyl ester-induced hypertension by treatment with carvedilol, an adrenergic blocker. Western blot analysis indicated that Cx43 was more phosphorylated in the aortae of the 2K1C rats mentioned above than in the animals receiving N w -nitro-Larginine methyl ester, indicating that there may be a different regulatory process for aortic Cx43 in the 2 models of hypertension 53 and emphasizing the potential importance of phosphorylation in the regulation of connexin function.…”

Descending vasa recta endothelium is an electrical syncytium

“…In contrast to the hypertension associated with Cx40 deletion, targeted deletion of Cx43 from the endothelium using the Cre recombinase approach has been reported to reduce blood pressure (34,49). In animal models of hypertension, expression of Cx43 has been reported to undergo variable regulation in both the peripheral and renal vasculature (24,25), and replacement of Cx43 with Cx32 is associated with decreased renin expression and resistance to two kidney-one clip hypertension (23).…”

“…Warm ischemia time after harvest of the kidney from the rat and before microdissection is limited to only a few minutes, but connexins are known to be rapidly inserted and retrieved from the cell membrane. Similarly, connexins are regulated by many factors such as phosphorylation events, pH, and elevation of [Ca 2ϩ ] cyt (8,15,19,24,52). Stimulation by agonists such as endothelin and angiotensin II affects opening of gap junctions so that residual effects of those and other hormones occurring in vivo may be responsible for setting the relative open state of myoendothelial junctions (30,31).…”

Connections in chronic kidney disease: connexin 43 and connexin 37 interaction

“…Cx43 mRNA in the heart is not altered 4 wk after 2K1C, DOCA-salt hypertension, or N -nitro-L-arginine methyl ester (L-NAME; nitric oxide inhibitor) hypertension. However, Cx43 protein expression is increased in the aorta of rats with 2K1C or DOCA-salt hypertension but decreased in rats with L-NAME hypertension (11). Cx43 has also been reported to be highly expressed in inflammatory, damaged renal tubule, interstitial cells in human kidneys (14), and podocytes of rats with puromycin aminonucleoside nephrosis (32).…”