Obesity-Induced Coronary Microvascular Disease Is Prevented by iNOS Deletion and Reversed by iNOS Inhibition

Shah, Soham A; Reagan, Claire E; Bresticker, Julia; Wolpe, Abigail G.; Good, Miranda E.; Macal, Edgar; Billcheck, Helen O.; Bradley, Leigh; French, Brent A.; Isakson, Brant E.; Wolf, Matthew J.; Epstein, Frederick H.

doi:10.1016/j.jacbts.2022.11.005

Cited by 5 publications

(10 citation statements)

References 48 publications

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“… 4 There are concerns that off-target effects may have an impact on beneficial endothelial NOS and neuronal NOS. iNOS inhibitors also reduce blood pressure (as seen in this study 1 as well), which can also improve CMD. It is not known whether the beneficial effects of iNOS inhibition are therefore caused by a decrease in systemic blood pressure or direct improvement in coronary microvascular function.…”

supporting

confidence: 72%

“…Basic scientists are working hard to close the gap. In a timely study by Shah et al 1 in this issue of JACC: Basic to Translational Science , the investigators leverage their extensive and robust prior efforts to develop quantitative coronary microvascular imaging methods to probe the underlying biology of CMD.…”

mentioning

confidence: 99%

“…By leveraging previously established tools that use arterial spin labeling cardiac magnetic resonance methods to quantify myocardial blood flow at rest and stress, Shah et al 1 show that C57BL/6J mice fed a high-fat high-sucrose diet develop CMD via an inducible nitric oxide synthase (iNOS)-dependent mechanism. They then administer selective iNOS inhibitor 1400X to improve MPR, establishing the role of iNOS in CMD and suggesting that iNOS inhibition may be a therapeutic option to consider for CMD.…”

mentioning

confidence: 99%

“…The hallmark of CMD is decreased MPR; however, decreased MPR can be caused by decreased stress blood flow or increased rest flow ( Figure 1 ). In their paper, Shah et al 1 focus on iNOS as a mechanism that affects the vasculature, blunts stress myocardial blood flow, and reduces MPR. Others have shown that MPR may be driven by increased resting flow, especially in the setting of increased metabolic insults.…”

mentioning

confidence: 99%

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Translational Insights in Coronary Microvascular Disease

Sharavana

Guerraty

2023

JACC: Basic to Translational Science

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supporting

confidence: 72%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Translational Insights in Coronary Microvascular Disease

Sharavana

Guerraty

2023

JACC: Basic to Translational Science

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“…8H), suggesting that Nox4 does not contribute to these hypertension models. Conversely, after HFHS feeding, which we and others have shown induces hypertension (81)(82)(83)(84)(85), there was decreased vascular Panx3 expression (Fig. 8I), coupled with reduced Bcl6 protein (without mRNA changes) (Fig.…”

Section: Discussionmentioning

confidence: 63%

Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress

Wolpe,

Luse,

Baryiames

et al. 2024

Sci. Signal.

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Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell–specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca 2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H 2 O 2 -producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H 2 O 2 -induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.

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