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Updated: Feb 19, 2026
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Selective ROCK2 inhibition reduces microvascular obstruction but does not reduce myocardial infarction after
Lucie Pearce1, David He1, Derek M Yellon1
1The Hatter Cardiovascular Institute, University College London, London, England, United Kingdom.
Introduction:
Myocardial ischaemia/reperfusion (I/R) injury causes infarction, microvascular obstruction (MVO), and haemorrhage. MVO, often driven by vasospasm, lacks effective therapy. The non-selective ROCK inhibitor fasudil, used for cerebral vasospasm, limits infarct size after myocardial I/R, but the roles of individual ROCK isoforms in limiting infarction and MVO remain unclear.
Aims:
To determine the contribution of ROCK2 to myocardial and microvascular obstruction and to assess the vasodilatory potential of ROCK2 inhibition.
Methods:
ROCK1/2 expression was analysed in rat hearts by RNAscope. Vascular myography assessed arterial responses to ROCK inhibitors. Rats underwent 30 min coronary occlusion and 180 min reperfusion, with ROCK2 inhibitor KD025 (100 mg/kg i.p.) or vehicle administered before reperfusion. Infarct size (%AAR) and MVO (%AAR) were quantified by TTC and Thioflavin S staining, respectively. Infarct size was also compared in WT and ROCK2+/- mice.
Results:
ROCK2 mRNA was more highly expressed than ROCK1 in both myocardium and coronary vasculature. The dual ROCK1/2 inhibitor, fasudil (10 mg/kg), reduced infarct size (34.5 ± 5.7 vs 55.8 ± 4.7%, P = 0.02, n = 6), whereas the ROCK2-selective KD025 (100 mg/kg) had no effect (43.7 ± 5.5 vs 48.3 ± 4.9%, P = 0.87, n = 8) and also showed no vasodilation ex vivo. ROCK2+/- mice were similar to WT. However, KD025 reduced MVO% in rats (21.8 ± 2.5 vs 32.2 ± 1.8%, P = 0.04, n = 8), as did 3 mg/kg fasudil (19.2 ± 4.1 vs 32.2 ± 1.8%, P = 0.01, n = 6).
Conclusion:
Dual ROCK1/2 inhibition protects myocardium from I/R injury, whereas selective ROCK2 inhibition or deficiency does not, implicating ROCK1 in infarct limitation. In contrast, ROCK2 inhibition reduced MVO, identifying ROCK2 as a potential microvascular target.
Insights
Dual ROCK1/2 inhibition protects the heart from injury, while ROCK2 inhibition specifically targets microvascular obstruction. This suggests ROCK1 is key for limiting infarct size and ROCK2 for improving microvascular function after ischemia/reperfusion.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Myocardial ischemia/reperfusion (I/R) injury leads to infarction and microvascular obstruction (MVO).
- Microvascular obstruction, often caused by vasospasm, currently lacks effective therapeutic strategies.
- The non-selective ROCK inhibitor fasudil has shown promise in limiting infarct size, but the specific roles of ROCK isoforms (ROCK1 and ROCK2) in I/R injury remain unclear.
Purpose of the Study:
- To investigate the contribution of ROCK2 to myocardial infarction and MVO following I/R injury.
- To evaluate the vasodilatory potential of ROCK2 inhibition.
- To elucidate the distinct roles of ROCK1 and ROCK2 in the context of myocardial I/R.
Main Methods:
- ROCK1 and ROCK2 expression levels were quantified in rat hearts using RNAscope.
- Vascular myography was employed to assess arterial responses to ROCK inhibitors.
- Rats underwent a 30-minute coronary occlusion followed by 180 minutes of reperfusion, with administration of a ROCK2 inhibitor (KD025) or vehicle prior to reperfusion. Infarct size and MVO were measured. Studies were also conducted in wild-type and ROCK2-deficient mice.
Main Results:
- ROCK2 mRNA exhibited higher expression than ROCK1 in both the myocardium and coronary vasculature.
- The dual ROCK1/2 inhibitor fasudil significantly reduced infarct size, whereas the ROCK2-selective inhibitor KD025 did not affect infarct size or demonstrate vasodilation.
- ROCK2 inhibition with KD025, however, effectively reduced MVO, similar to the effect of fasudil.
Conclusions:
- Dual inhibition of ROCK1 and ROCK2 protects the myocardium against I/R injury, indicating a role for ROCK1 in infarct limitation.
- Selective ROCK2 inhibition or deficiency does not limit infarct size, suggesting ROCK1 is the primary isoform involved in this protective effect.
- ROCK2 inhibition demonstrates efficacy in reducing MVO, identifying ROCK2 as a potential therapeutic target for microvascular dysfunction in myocardial I/R injury.
