Improving myocardial fractional flow reserve in coronary atherosclerosis via CX37 gene silence: a preclinical validation study in pigs

Guo, Suxia; Yang, Ying; Yang, Zhenyu; You, Huayan; Shi, Yugen; Hu, Zhao; Meng, Zhen; Xiao, Jianying

doi:10.1093/icvts/ivx218

Cited by 3 publications

(2 citation statements)

References 24 publications

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“…Moreover, our findings indicate mechanisms potentially more or less involved in the vascular effects of sex hormones, in this case estradiol. In contrast to the favorable effect of estradiol on aortic strain and expression of Nos3 , there was no effect of the ovariectomy and/or estradiol substitution on the expression of also “cardiovascular” gene for Cx37 [ 18 , 19 ], which is potential target for intervention in cardiovascular disease [ 20 ] and described as important for cardiovascular disease in previous (but not all) studies [ 21 , 22 , 23 , 24 ]. The explanation for this negative finding could be that the change of Cx37 gene expression was not yet detectable relatively soon after ovariectomy and could be relatively delayed compared to the change of the expression of gene for Nos3 .…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats

Piťha

Hüttl

Malínská

et al. 2022

IJMS

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Background: If menopause is really independent risk factor for cardiovascular disease is still under debate. We studied if ovariectomy in the model of insulin resistance causes cardiovascular changes, to what extent are these changes reversible by estradiol substitution and if they are accompanied by changes in other organs and tissues. Methods: Hereditary hypertriglyceridemic female rats were divided into three groups: ovariectomized at 8th week (n = 6), ovariectomized with 17-β estradiol substitution (n = 6), and the sham group (n = 5). The strain of abdominal aorta measured by ultrasound, expression of vascular genes, weight and content of myocardium and also non-cardiac parameters were analyzed. Results: After ovariectomy, the strain of abdominal aorta, expression of nitric oxide synthase in abdominal aorta, relative weight of myocardium and of the left ventricle and circulating interleukin-6 decreased; these changes were reversed by estradiol substitution. Interestingly, the content of triglycerides in myocardium did not change after ovariectomy, but significantly increased after estradiol substitution while adiposity index did not change after ovariectomy, but significantly decreased after estradiol substitution. Conclusion: Vascular and cardiac parameters under study differed in their response to ovariectomy and estradiol substitution. This indicates different effects of ovariectomy and estradiol on different cardiovascular but also extracardiac structures.

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Section: Discussionmentioning

confidence: 99%

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats

Piťha

Hüttl

Malínská

et al. 2022

IJMS

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“…These results suggest that Cx37 may play an important role in the development of AS vulnerable plaques, and inhibition of its expression can reverse vulnerable plaques. In the follow-up study, the researcher further observed the effect of siRNA Cx37 transfection on the fractional fow reserve (FFR) of porcine myocardium, and the results showed that after Cx37 siRNA interference, FFR was significantly improved [ 11 ], suggesting that inhibition of Cx37 expression can inhibit the progression of AS and improve overall cardiac function. Therefore, the correlation between Cx37 and AS has been confirmed from clinical disease genetics detection and animal experiments, and Cx37 is expected to become a potential target to curb the occurrence and development of AS.…”

Section: Introductionmentioning

confidence: 99%

Connexin 37 Regulates the Kv1.3 Pathway and Promotes the Development of Atherosclerosis

Liao

Chen

et al. 2022

Mediators of Inflammation

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Objective. To investigate the mechanism of Connexin 37 (Cx37) and Kv1.3 pathways in atherosclerosis (AS). Methods. ApoE-/- mice were given a high-fat diet to establish atherosclerosis (AS) model, and macrophages in mice were isolated and extracted to transfect Cx37 vectors with silencing or overexpressing, and Kv1.3 pathway blockers were used to inhibit the pathway activity. The indexes of body weight, blood glucose, and blood lipid of mice were collected. The protein and mRNA expression levels of Cx37 and Kv1.3 were detected by reverse transcription-PCR (RT-PCR), Western blot, and immunofluorescence technique. Oil red O staining was used to observe plaque area. Masson staining was used to detect collagen content. The concentrations of chemokine CCL7 were quantified using the ELISA kits. CCK8 was used to detect cell proliferation. Results. Cx37 and Kv1.3 were highly expressed in macrophages of AS mice, and the expression of Kv1.3 and CCL7 decreased after Cx37 was silenced, and the proliferation of macrophages was also decreased. Wild-type mice and AS model mice were treated with Cx37 overexpression vectors and Kv1.3 pathway blocking, and it was found that Cx37 overexpression could improve the blood lipid and blood glucose levels and increase the area of AS in AS mice. However, blocking the activity of Kv1.3 pathway can reduce the levels of blood lipid and blood glucose, increase the body weight of mice, and reduce the area of AS mice. Blocking the activity of Kv1.3 pathway can slow down the plaque development of AS mice and make its indexes close to wild-type mice. And the use of Kv1.3 pathway blockers on the basis of overexpression of Cx37 indicated that inhibition of Kv1.3 pathway activity did not affect the expression of Cx37, but could inhibit the collagen content in the plaque area of AS mice, inhibit the expression of chemokine CCL7, and reverse the effect of Cx37 overexpression. Conclusion. Cx37 can improve the activity of macrophages by regulating the expression of chemokines and the activity of Kv1.3 pathway in AS mice, and enrich macrophages in inflammatory tissues and expand the area of plaque formation.

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Connexins: Key Players in the Control of Vascular Plasticity and Function

Pohl

2020

Physiological Reviews

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Of the 21 members of the connexin family, 4 (Cx37, Cx40, Cx43, and Cx45) are expressed in the endothelium and/or smooth muscle of intact blood vessels to a variable and dynamically regulated degree. Full-length connexins oligomerize and form channel structures connecting the cytosol of adjacent cells (gap junctions) or the cytosol with the extracellular space (hemichannels). The different connexins vary mainly with regard to length and sequence of their cytosolic COOH-terminal tails. These COOH-terminal parts, which in the case of Cx43 are also translated as independent short isoforms, are involved in various cellular signaling cascades and regulate cell functions. This review focuses on channel-dependent and -independent effects of connexins in vascular cells. Channels play an essential role in coordinating and synchronizing endothelial and smooth muscle activity and in their interplay, in the control of vasomotor actions of blood vessels including endothelial cell reactivity to agonist stimulation, nitric oxide-dependent dilation, and endothelial-derived hyperpolarizing factor-type responses. Further channel-dependent and -independent roles of connexins in blood vessel function range from basic processes of vascular remodeling and angiogenesis to vascular permeability and interactions with leukocytes with the vessel wall. Together, these connexin functions constitute an often underestimated basis for the enormous plasticity of vascular morphology and function enabling the required dynamic adaptation of the vascular system to varying tissue demands.

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Improving myocardial fractional flow reserve in coronary atherosclerosis via CX37 gene silence: a preclinical validation study in pigs

Abstract: Our study showed that FFR levels increased along with decreased doses of siRNA CX37 lentivirus, indicating that siRNA CX37 lentivirus may reduce the risk of coronary atherosclerosis and provide a potential approach to treat coronary heart disease.

Cited by 3 publications

References 24 publications

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats

Cardiovascular, Metabolic and Inflammatory Changes after Ovariectomy and Estradiol Substitution in Hereditary Hypertriglyceridemic Rats

Connexin 37 Regulates the Kv1.3 Pathway and Promotes the Development of Atherosclerosis

Connexins: Key Players in the Control of Vascular Plasticity and Function

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