bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.11.28.518274

Repurposing antihypertensive, lipid-lowering and antidiabetic drugs for lacunar stroke

Zhang, L.·Huang, T.·Fan, D.
View original source ↗Export metadata ↓

Abstract

BackgroundTo estimate the causal associations of modifiable risk factors with lacunar stroke (LS) and repurposing of common antihypertensive, lipid-lowering and antidiabetic drugs to prevent LS. MethodsThe effects of common antihypertensive, lipid-lowering and antidiabetic drugs on LS were estimated using a drug-target Mendelian randomization (MR) approach. LS data for the transethnic analysis were derived from meta-analyses comprising 7,338 cases and 254,798 controls. FindingsGenetically predicted hypertension and type 2 diabetes significantly increased LS risk. Elevated triglyceride and apolipoprotein B levels caused a 14% increased LS risk, while elevated apolipoprotein A-I and high-density lipoprotein levels caused a 12% decreased risk. Elevated triglyceride levels remained significantly associated with a higher LS risk in multivariable MR analysis (OR, 1.21; 95% CI, 1.06-1.40, P =0.005). Drug-target MR demonstrated that genetic variants mimicking calcium channel blockers most stably prevented LS (OR, 0.75; 95% CI, 0.61-0.92, P =0.006). The genetic variants at or near HMGCR (i.e., mimicking the effect of statins), NPC1L1 (mimicking the effects of ezetimibe) and APOC3 (mimicking antisense anti-apoC3 agents) were predicted to decrease LS incidence. Genetically proxied GLP1R agonism showed a marginal effect on LS, while a genetically proxied improvement in overall glycemic control was associated with a reduced LS risk (OR, 0.94; 95% CI, 0.92-0.96; P=4.58x10-7). InterpretationRepurposing several drugs with well-established safety and low costs for LS prevention in clinical practice may contribute to healthier brain aging. FundingThis study was supported by National Natural Science Foundation of China (grant numbers 8210051863).

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Zhang, L., Huang, T., Fan, D.. 2022-11-29. Repurposing antihypertensive, lipid-lowering and antidiabetic drugs for lacunar stroke. https://doi.org/10.1101/2022.11.28.518274

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗
bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗
bioRxiv2026

Innate immune stress pathway activation underlies heterochromatin dysfunction pathology

Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.

genetics↗