Table 5.

Evidence of pyroptosis in MI/R injury: rreports from in vivo studies.

Disease Condition		Model	Pyroptotic marker				IS%	LV function	Cardiac injury	Inflammatory marker/ROS	Other cell death markers/Relevant findings	Interpretation	Ref.
I	R		GSDMD		Caspase-1	Others
			Active form	Full form
0.5 h	2 h	Kunming mice	–	↑	↑	↑ ASC ↑ NLRP3	↑	–	↑ CK-MB ↑ LDH	↑ IL-1β	↑ TUNEL ↑ Caspase-3	I/R activated GSDMD in canonical pathway, leading to pyroptosis, apoptosis, cardiac injury and infarction.	42, 43
0.5 h	2 h	SD rats	↑	↔	–	–	↑	–	–	↑ IL-1β	↑ Disordered and swollen myocardial cells	I/R activated GSDMD-N, leading to pyroptosis, and infarction.	42, 43
0.5 h	2 h	SD rats	↑	↔	–	↑ ASC ↑ NLRP3	↑	–	↑ CK ↑ CK-MB ↑ LDH	↑ TXNIP ↑ TLR4 ↑ MYD88 ↑ p-IκBα ↑ p-NF-κB ↑ IL-1β ↑ IL-18	↓ miR-148a ↑ IP3R ↑ SERCA2a ↑ Ca2+ overload ↑ Disordered and swollen cells	I/R increased oxidative stress through miR-148a/TXNIP axis to activate GSDMD in canonical pathway, resulting in pyroptosis, calcium overload, and infarction.	42, 43
0.5 h	2 h	SD rats	↑	↑	↑	↑ ASC ↑ NLRP3	↑	↓ %EF ↓ %FS ↑ E/A	–	↑ IL-1β ↑ IL-6 ↑ TNF-α	↑ HMGB1	Upregulation of HMGB1 induced by I/R activated GSDMD in canonical pathway, leading to pyroptosis, cytokine release, infarction, and LV dysfunction.	42, 43
0.5 h	24 h	SD rats	–	↑	↑	↑ ASC ↑ NLRP3	↑	–	–	↑ IL-1β ↑ IL-18	↑ TUNEL ↑ Periostin ↑ Inflammatory cells infiltration ↑ Myocardial ell swelling & degeneration	I/R activated GSDMD in canonical pathway, leading to pyroptosis, inflammatory cells in filtration, and infarction.	42, 43
45 min	6 h	C57BL/6 mice	–	↑	↑	↑ NLRP3	↑	–	↑ CK ↑ CK-MB ↑cTnI ↑ LDH	–	↑ TUNEL ↑ Neutrophils and macrophages infiltration ↓ %Survival rate	I/R activated GSDMD in canonical pathway, leading to pyroptosis, cardiac injury and infarction.	42, 43
45 min	24 h	SD rats	↑	↑	↑	↑ ASC ↑ NLRP3	–	↓ %EF ↓ %FS ↑ LVIDd ↑ LVIDs	↑ cTNT ↑ MPO	↑ IL-1β	–	I/R activated GSDMD in canonical pathway, leading to pyroptosis, cardiac injury and LV dysfunction.	42, 43
45 min	48 h	C57BL/6 mice	↑	↔	↑	↑ NLRP3	–	–	↑ BNP ↓ α-MHC ↑ β-MHC ↑ CK-MB ↑ cTnI ↑ LDH	↑ TLR4 ↑ MYD88 ↑ p-NF-κB/NF-κB ↑ IL-1β ↑ IL-6 ↑ TNF-α	↑ lncRNA Pvt 1 ↑ BAX ↓ Bcl-2 ↑ c-Caspase-3	I/R increased lncRNA Pvt 1 to activate GSDMD in canonical pathway, leading to pyroptosis, apoptosis, cytokine release, and cardiac injury, which was confirmed by genetic inhibition.	42, 43
		C57BL/6 mice + sh-Pvt1 vs. WT-I/R	↓	↔	↓	↓ NLRP3	–	–	↓ BNP ↑ α-MHC ↓ β-MHC ↓ CK-MB ↓ cTnI ↓ LDH	↓ TLR4 ↓ MYD88 ↓ p-NF-κB/NF-κB ↓ IL-1β ↓ IL-6 ↑ TNF-α	↓ lncRNA Pvt 1 ↓ Bax ↑ Bcl-2 ↓ c-Caspase-3
1 h	24 h	SD rats	↑	–	↑	↑ ASC ↑ NLRP3	–	↓ %EF ↓ %FS	↑ cTnI	↑ IL-1β ↑ ROS ↑ MDA ↑ 8-OHDG	↑ Mitochondrial damage	I/R increased oxidative stress to activate GSDMD in canonical pathway, leading to pyroptosis, mitochondrial damage, cardiac injury, and LV dysfunction,	42, 43
0.5 h	3 h	C57BL/6 mice	↔	↔	–	↔ GSDME ↔ Caspase-11	–	–	–	–	–	I/R activated GSDMD in non-canonical pathway, leading to pyroptosis in the early phase of reperfusion. However, GSDME had no role in I/R.	42, 43
	12 h		↑	↑	–	↔ GSDME ↑ Caspase-11	–	–	–	–	–
	24 h		↑	↑	–	↔ GSDME ↑ Caspase-11	–	–	–	–	–

Abbreviations: 8-OHDG: 8-hydroxy-2′-deoxyguanosine; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; BAX: Bcl-2 associated X protein; Bcl-2: B-cell lymphoma-2; BNP: B-type natriuretic peptide; c-caspase: cleaved caspase; CK: creatine kinase; CK-MB: creatine kinase myocardial band; cTnI: cardiac Troponin I; cTnT: cardiac Troponin T; E/A: mitral early diastolic flow/late diastolic flow velocity; %EF: left ventricular ejection fraction; FS%: left ventricular fractional shortening; GSDMD: Gasdermin D; GSDME: Gasdermin E; HMGB1: high mobility group box 1 protein; I: ischemia by coronary artery ligation; I/R: ischemia/reperfusion; IκBα: nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha; IL: interleukin; IP3R: type 3 inositol 1,4,5-trisphosphate receptor; %IS: %infarct size/area at risk; LDH: lactate dehydrogenase; LncRNA: long non-coding RNA; LV: left ventricle; LVIDd: LV internal dimension at end-diastole; LVIDs: LV internal dimension at end-systole; MDA: malondialdehyde; MHC: myosin heavy chain; MI: myocardial ischemia; miR: microRNA; MYD88: myeloid differentiation factor 88; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; NLRP3: NACHT, LRR and PYD domains-containing protein 3; p-IκBα: phosphorylated IκBα; p-NF-κB: phosphorylated NF-κB; Pvt 1: plasmacytoma variant translocation 1; R: reperfusion; RIPK3: receptor-interacting protein kinase 3; ROS: reactive oxygen species; SD rats: Sprague–Dawley rats; SERCA2a: sarco/endoplasmic reticulum Ca²⁺-ATPase 2a; sh-: short hairpin; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor alpha; TXNIP: thioredoxin-interacting protein TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling; WT: wild-type.