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Remuscularization with triiodothyronine and β₁-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

ABSTRACT: Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β₁-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone) accentuates the ability of T3 to stimulate ERK1/2 phosphorylation and proliferative signaling by inhibiting expression of the nuclear phospho-ERK1/2-specific phosphatase, dual-specificity phosphatase-5. While short-duration metoprolol plus T3 therapy generates new heart muscle in healthy mice, in mice with myocardial infarction-induced left ventricular dysfunction and pathological remodeling, it remuscularizes the heart, restores contractile function and reverses chamber dilatation; outcomes that are enduring. If the beneficial effects of metoprolol plus T3 are replicated in humans, this therapeutic strategy has the potential to definitively address ischemic heart failure.

SUBMITTER: Bogush N

PROVIDER: S-EPMC9132945 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Remuscularization with triiodothyronine and β<sub>1</sub>-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

Bogush Nikolay N Tan Lin L Naqvi Emmen E Calvert John W JW Graham Robert M RM Taylor W Robert WR Naqvi Nawazish N Husain Ahsan A

Scientific reports 20220525 1

Renewal of the myocardium by preexisting cardiomyocytes is a powerful strategy for restoring the architecture and function of hearts injured by myocardial infarction. To advance this strategy, we show that combining two clinically approved drugs, but neither alone, muscularizes the heart through cardiomyocyte proliferation. Specifically, in adult murine cardiomyocytes, metoprolol, a cardioselective β<sub>1</sub>-adrenergic receptor blocker, when given with triiodothyronine (T3, a thyroid hormone ...[more]

PMID: 35614155

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Project description:Heme oxygenase-1 (Hmox1) is a stress-inducible protein crucial in heme catabolism. The end products of its enzymatic activity possess anti-oxidative, anti-apoptotic and anti-inflammatory properties. Cardioprotective effects of Hmox1 were demonstrated in experimental models of myocardial infarction (MI). Nevertheless, its importance in timely resolution of post-ischemic inflammation remains incompletely understood. The aim of this study was to determine the role of Hmox1 in the monocyte/macrophage-mediated cardiac remodeling in a mouse model of MI. Hmox1 knockout (Hmox1-/-) and wild-type (WT, Hmox1+/+) mice were subjected to a permanent ligation of the left anterior descending coronary artery. Significantly lower incidence of left ventricle (LV) free wall rupture was noted between 3rd and 5th day after MI in Hmox1-/- mice resulting in their better overall survival. Then, starting from 7th until 21st day post-MI a more potent deterioration of LV function was observed in Hmox1-/- than in the surviving Hmox1+/+ mice. This was accompanied by higher numbers of Ly6Chi monocytes in peripheral blood, as well as higher expression of monocyte chemoattractant protein-1 and adhesion molecules in the hearts of MI-operated Hmox1-/- mice. Consequently, a greater post-MI monocyte-derived myocardial macrophage infiltration was noted in Hmox1-deficient individuals. Splenectomy decreased the numbers of circulating inflammatory Ly6Chi monocytes in blood, reduced the numbers of proinflammatory cardiac macrophages and significantly improved the post-MI LV function in Hmox1-/- mice. In conclusion, Hmox1 deficiency has divergent consequences in MI. On the one hand, it improves early post-MI survival by decreasing the occurrence of cardiac rupture. Afterwards, however, the hearts of Hmox1-deficient mice undergo adverse late LV remodeling due to overactive and prolonged post-ischemic inflammatory response. We identified spleen as an important source of these cardiovascular complications in Hmox1-/- mice.

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Remuscularization with triiodothyronine and β₁-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

Publications

Remuscularization with triiodothyronine and β<sub>1</sub>-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

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Remuscularization with triiodothyronine and β1-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

Publications

Remuscularization with triiodothyronine and β<sub>1</sub>-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Remuscularization with triiodothyronine and β₁-blocker therapy reverses post-ischemic left ventricular dysfunction and adverse remodeling.