Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood-brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging.

Long non-coding RNAs (lncRNAs) contribute to cardiac (patho)physiology. Aging is the major risk factor for cardiovascular disease with cardiomyocyte apoptosis as one underlying cause. Here, we report the identification of the aging-regulated lncRNA Sarrah (ENSMUST00000140003) that is anti-apoptotic in cardiomyocytes. Importantly, loss of SARRAH (OXCT1-AS1) in human engineered heart tissue results in impaired contractile force development. SARRAH directly binds to the promoters of genes downregulated after SARRAH silencing via RNA-DNA triple helix formation and cardiomyocytes lacking the triple helix forming domain of Sarrah show an increase in apoptosis. One of the direct SARRAH targets is NRF2, and restoration of NRF2 levels after SARRAH silencing partially rescues the reduction in cell viability. Overexpression of Sarrah in mice shows better recovery of cardiac contractile function after AMI compared to control mice. In summary, we identified the anti-apoptotic evolutionary conserved lncRNA Sarrah, which is downregulated by aging, as a regulator of cardiomyocyte survival.

Aging is accompanied by many physiological changes. These changes can progressively lead to many types of cardiovascular diseases. During this process blood vessels lose their ability to maintain vascular homeostasis, ultimately resulting in hypertension, stroke, or myocardial infarction. Increase in DNA damage is one of the hallmarks of aging and can be repaired by the DNA signaling and repair system. In our study we show that long non-coding RNA Aerrie (linc01013) contributes to the DNA signaling and repair mechanism. Silencing of Aerrie in endothelial cells impairs angiogenesis, migration, and barrier function. Aerrie associates with YBX1 and together they act as important factors in DNA damage signaling and repair. This study identifies Aerrie as a novel factor in genomic stability and as a binding partner of YBX1 in responding to DNA damage.