Abstract
AimsWe have previously demonstrated protection against obesity, metabolic dysfunction, atherosclerosis and cardiac ischemia in a hypoxia-inducible factor (HIF) prolyl 4-hydroxylase-2 (Hif-p4h-2) deficient mouse line, attributing these protective effects to activation of the hypoxia response pathway in a normoxic environment. We intended here to find out whether the Hif-p4h-2 deficiency affects the cardiac health of these mice upon aging. Methods and resultsWhen the Hif-p4h-2 deficient mice and their wild-type littermates were monitored during normal aging, the Hif-p4h-2 deficient mice had better preserved diastolic function than the wild type at one year of age and less cardiomyocyte hypertrophy at two years. On the mRNA level, downregulation of hypertrophy-associated genes was detected and shown to be associated with upregulation of Notch signaling, and especially of the Notch target gene and transcriptional repressor Hairy and enhancer-of-split-related basic helix-loop-helix (Hey2). Blocking of Notch signaling in cardiomyocytes isolated from Hif-p4h-2 deficient mice with a gamma-secretase inhibitor led to upregulation of the hypertrophy-associated genes. Also, targeting Hey2 in isolated wild-type rat neonatal cardiomyocytes with siRNA led to upregulation of hypertrophic genes and increased leucine incorporation indicative of increased protein synthesis and hypertrophy. Finally, oral treatment of wild-type mice with a small molecule inhibitor of HIF-P4Hs phenocopied the effects of Hif-p4h-2 deficiency with less cardiomyocyte hypertrophy, upregulation of Hey2 and downregulation of the hypertrophy-associated genes. ConclusionsThese results indicate that activation of the hypoxia response pathway upregulates Notch signaling and its target Hey2 resulting in transcriptional repression of hypertrophy-associated genes and less cardiomyocyte hypertrophy. This is eventually associated with better preserved cardiac function upon aging. Activation of the hypoxia response pathway thus has therapeutic potential for combating age-induced cardiac hypertrophy.
Highlights
Cardiovascular diseases are the leading cause of death on a global scale [1], and cardiac impairments of varying etiology are estimated to affect over 37 million people [2]
When we re-evaluated the data by comparing cardiac function in 4-week-old and one-year-old mice it pointed to a deterioration in diastolic function in the wild-type mice whereas the Hif-p4h-2 deficient mice were protected against this deterioration (Supplemental Fig. 1A, Table 1)
We allowed a cohort of male Hif-p4h-2 deficient mice and their wild-type littermates to age until a humane end-point was reached
Summary
Cardiovascular diseases are the leading cause of death on a global scale [1], and cardiac impairments of varying etiology are estimated to affect over 37 million people [2]. Heart failure is commonly caused by chronically increased cardiac workload, leading to a loss of cardiomyocytes or pressure overload due to hypertension. In response to increased loading, the heart undergoes pathophysiological processes, characterized by structural and functional remodeling of the myocar dium, such as cardiomyocyte hypertrophy and fibrosis [3,4]. The prevalence of heart failure increases dramatically upon aging [5], and increased arterial stiffness [6], elevated blood pressure [7], T. Decreased inotropic responsiveness, reduced diastolic filling and endo thelial dysfunction [8] have all been suggested to contribute to the decline in cardiac function during physiological aging [9]. Several distinct molecular pathways contribute to cardiac remodeling; sustained inflammation due to upregulated cytokine release leads to fibroblast proliferation and metalloproteinase activation [10]. Increased oxidative stress and altered energy metabolism both support hypertrophic and fibrotic processes [11]
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