Dataset Information

Constitutive protein kinase G activation exacerbates stress-induced cardiomyopathy.

ABSTRACT:

Background and purpose

Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodelling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed and the effects of long-term PKG activation in the heart are unknown.

Experimental approach

We characterized the cardiac phenotype of mice carrying a heterozygous knock-in mutation of PKG1 (Prkg1^R177Q/+ ), which causes constitutive, cGMP-independent activation of the kinase. We examined isolated cardiac myocytes and intact mice, the latter after stress induced by surgical transaortic constriction or angiotensin II (Ang II) infusion.

Key results

Cardiac myocytes from Prkg1^R177Q/+ mice showed altered phosphorylation of sarcomeric proteins and reduced contractility in response to electrical stimulation, compared to cells from wild type mice. Under basal conditions, young PKG1^R177Q/+ mice exhibited no obvious cardiac abnormalities, but aging animals developed mild increases in cardiac fibrosis. In response to angiotensin II infusion or fixed pressure overload induced by transaortic constriction, young PKG^R177Q/+ mice exhibited excessive hypertrophic remodelling with increased fibrosis and myocyte apoptosis, leading to increased left ventricular dilation and dysfunction compared to wild type litter mates.

Conclusion and implications

Long-term PKG1 activation in mice may be harmful to the heart, especially in the presence of pressure overload and neurohumoral stress.

Linked articles

This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

SUBMITTER: Schwaerzer GK

PROVIDER: S-EPMC9926932 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Constitutive protein kinase G activation exacerbates stress-induced cardiomyopathy.

Schwaerzer Gerburg K GK Casteel Darren E DE Cividini Federico F Kalyanaraman Hema H Zhuang Shunhui S Gu Yusu Y Dalton Nancy D ND Peterson Kirk L KL Dillmann Wolfgang H WH Boss Gerry R GR Pilz Renate B RB

British journal of pharmacology 20210621 11

<h4>Background and purpose</h4>Heart failure is associated with high morbidity and mortality, and new therapeutic targets are needed. Preclinical data suggest that pharmacological activation of protein kinase G (PKG) can reduce maladaptive ventricular remodelling and cardiac dysfunction in the stressed heart. However, clinical trial results have been mixed and the effects of long-term PKG activation in the heart are unknown.<h4>Experimental approach</h4>We characterized the cardiac phenotype of ...[more]

PMID: 34000062

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Project description:Background and purposeWhile maintaining cardiac performance, chronic ?-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic ??-adrenoceptor activation.Experimental approachMice with transgenic ??-adrenoceptor overexpression (??-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared.Key results??-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. ??-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of ??-TG mice. NAC treatment (500 mg·kg?¹ ·day?¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of ??-TG mice. Chronic NAC treatment to ??-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity.Conclusion and implications??-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.

Dataset Information

Constitutive protein kinase G activation exacerbates stress-induced cardiomyopathy.

Background and purpose

Experimental approach

Key results

Conclusion and implications

Linked articles

Publications

Constitutive protein kinase G activation exacerbates stress-induced cardiomyopathy.

Similar Datasets

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