Luteolin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Modulating AMPK/HO-1-Mediated Oxidative Stress and Inflammatory Responses

Q: What are the key findings of this study?

Luteolin (100 mg/kg/day) significantly attenuated isoproterenol-induced cardiac hypertrophy, oxidative stress, and inflammation in rats and H9c2 cells via AMPK/HO-1 signaling (p<0.05).

Q: What is the clinical evidence from this study?

Population: Isoproterenol-induced cardiac hypertrophy (n=30). Intervention: Luteolin vs. Isoproterenol alone (5 mg/kg/day subcutaneously in vivo; 10 µM in vitro) and 0.9% saline vehicle control. Primary outcome: Attenuation of isoproterenol-induced cardiac hypertrophy (heart weight-to-body weight ratio, ventricular wall thickness, cardiomyocyte cross-sectional area, and hypertrophic markers ANP, BNP, β-MHC) (p=<0.05).

Q: What question did this study set out to answer?

To investigate the protective effects and molecular mechanisms of luteolin against isoproterenol-induced cardiac hypertrophy in animal and cellular models.

Yipin Zhao; Zebin Lin; Guoxing Li; Yingjie Zhao; Xinlong Di; Jianmin Tang; Xiaohu Wang; Shengfang Wang

doi:10.21203/rs.3.rs-10986376/v1

September 30, 2026Open Access

Luteolin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Modulating AMPK/HO-1-Mediated Oxidative Stress and Inflammatory Responses

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Key result

Luteolin attenuates isoproterenol-induced cardiac hypertrophy and inflammation via AMPK/HO-1 signaling in preclinical models.

P<0.05
n=30

Why the study?

Luteolin is a flavonoid with antioxidant and anti-inflammatory properties, but its molecular regulation of pathological cardiac hypertrophy remained incompletely understood.

Does luteolin attenuate isoproterenol-induced cardiac hypertrophy, inflammation, and oxidative stress in male Sprague-Dawley rats and H9c2 cardiomyoblasts?

Key Points

To investigate the protective effects and molecular mechanisms of luteolin against isoproterenol-induced cardiac hypertrophy in animal and cellular models.
Administered isoproterenol for 14 days in male Sprague-Dawley rats with or without luteolin to assess cardiac remodeling, histological changes, and serum cytokine levels.
Treated cultured H9c2 cardiomyoblasts with isoproterenol and luteolin (10 µM) alongside pharmacological inhibitors (Compound C, ZnPPIX) or siRNA knockdown targeting AMPK or HO-1.
Luteolin attenuated isoproterenol-induced increases in heart weight-to-body weight ratio, left ventricular wall thickness, cardiomyocyte cross-sectional area, collagen deposition, and ANP, BNP, and β-MHC expression.
Treatment significantly decreased IL-1β, IL-6, and TNF-α levels, reduced reactive oxygen species, MDA, and LDH accumulation, and restored SOD activity both in vivo and in vitro.
Luteolin restored AMPK phosphorylation (peaking at approximately 4 h) and sequentially upregulated HO-1 expression (peaking at approximately 12 h); inhibition or knockdown of AMPK or HO-1 partially abolished these protective effects.

Structured PICO

Does luteolin attenuate isoproterenol-induced cardiac hypertrophy, inflammation, and oxidative stress in male Sprague-Dawley rats and H9c2 cardiomyoblasts?

P

Population

30 male Sprague-Dawley rats (7-8 weeks old, ~200 g) and H9c2 cardiomyoblasts in an experimental model of isoproterenol-induced cardiac hypertrophy treated for 14 days.

I

Intervention

In vivo: Luteolin 100 mg/kg/day by oral gavage given concurrently with subcutaneous isoproterenol (5 mg/kg/day) for 14 days. In vitro: Luteolin 10 µM added to H9c2 cells treated with isoproterenol (10 µM) for 24 hours, with or without AMPK/HO-1 inhibitors (Compound C 25 µM, ZnPPIX 10 µM) or siRNA knockdown.

C

Comparator

In vivo: Isoproterenol group (subcutaneous ISO 5 mg/kg/day for 14 days) and Control group (equivalent volumes of 0.9% saline by subcutaneous and oral gavage routes for 14 days). In vitro: Untreated control cells, ISO-only (10 µM) treated cells, and positive control group treated with AICAR (1 mM) plus ISO (10 µM).

O

Outcome

Cardiac hypertrophy and structural remodeling assessed at 14 days in vivo (heart weight-to-body weight ratio, echocardiographic left ventricular anterior and posterior wall thickness and internal diameter, cardiomyocyte cross-sectional area, collagen deposition, and myocardial ANP, BNP, and β-MHC protein/mRNA expression) and at 24 hours in vitro (H9c2 cell surface area and ANP, BNP, and β-MHC expression).surrogate

Main Result

p-value: p=<0.05

This preclinical study demonstrates that luteolin attenuates β-adrenergic stress-induced pathological cardiac hypertrophy, oxidative injury, and inflammation in rats and cardiomyoblasts via sequential activation of the AMPK/HO-1 signaling pathway.

Limitations

H9c2 cardiomyoblasts do not fully reproduce the phenotype, contractile apparatus, and hypertrophic signaling of adult cardiomyocytes.
All pathway-perturbation experiments (Compound C, ZnPPIX, siRNA knockdown, AICAR positive control, and time-course analysis) were performed exclusively in H9c2 cells, leaving in vivo findings correlative.
Only male rats were studied to avoid estrous-cycle hormonal fluctuations, limiting generalizability to females.
The AICAR positive control was applied only in H9c2 cells and was not validated in vivo.
Direct binding of luteolin to AMPK or upstream kinases (LKB1, CaMKKβ) was not demonstrated, and parallel pathways like Nrf2 or SIRT1 cannot be excluded.
No a priori statistical power calculation was performed for the animal group size.
No a priori statistical power calculation was performed for group size
Oral bioavailability of luteolin is limited, and exposure to purified luteolin in experimental models cannot be assumed to represent habitual dietary intake

Implication

Should not yet change clinical practice; hypothesis-generating for luteolin in human cardiac hypertrophy.

Abstract

Luteolin is a naturally occurring flavonoid with antioxidant and anti-inflammatory properties; however, its molecular regulation of pathological cardiac hypertrophy remains incompletely understood. Here, we investigated the effects and mechanisms of luteolin in an isoproterenol (ISO)-induced model of cardiac hypertrophy using male Sprague-Dawley rats and H9c2 cardiomyoblasts. Luteolin treatment attenuated ISO-induced cardiac hypertrophy, ventricular wall thickening, cardiomyocyte enlargement, collagen deposition, and the expression of hypertrophic markers. In parallel, luteolin reduced inflammatory cytokine production and oxidative stress in both animal and cellular models. Mechanistic experiments demonstrated that luteolin restored AMP-activated protein kinase (AMPK) phosphorylation and enhanced heme oxygenase-1 (HO-1) expression. Pharmacological inhibition and siRNA-mediated silencing of AMPK or HO-1 partially abolished the protective effects of luteolin against hypertrophic responses, inflammation, and oxidative injury. Time-course analysis further indicated that AMPK activation preceded HO-1 induction, supporting a potential AMPK/HO-1 signaling cascade. Collectively, these findings reveal that luteolin protects against β-adrenergic stress-induced cardiac remodeling through regulation of inflammatory and oxidative responses and identify AMPK/HO-1 signaling as an important molecular mechanism underlying its cardioprotective effects.

Discussion

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Cite This Study

Zhao et al. (2026) studied Isoproterenol-induced cardiac hypertrophy (n=30). Luteolin vs. Isoproterenol alone (5 mg/kg/day subcutaneously in vivo; 10 µM in vitro) and 0.9% saline vehicle control was evaluated on Attenuation of isoproterenol-induced cardiac hypertrophy (heart weight-to-body weight ratio, ventricular wall thickness, cardiomyocyte cross-sectional area, and hypertrophic markers ANP, BNP, β-MHC) (p=<0.05). Luteolin (100 mg/kg/day) significantly attenuated isoproterenol-induced cardiac hypertrophy, oxidative stress, and inflammation in rats and H9c2 cells via AMPK/HO-1 signaling (p<0.05).

synapsesocial.com/papers/6ae28f53cbadf70daf6c44e4 https://doi.org/10.21203/rs.3.rs-10986376/v1

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Luteolin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Modulating AMPK/HO-1-Mediated Oxidative Stress and Inflammatory Responses

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Luteolin Protects Against Isoproterenol-Induced Cardiac Hypertrophy by Modulating AMPK/HO-1-Mediated Oxidative Stress and Inflammatory Responses

Key Points

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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