Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes.

Hypertrophic cardiomyopathy is the most common cardiovascular disease, which is characterized by structural and functional myocardial abnormalities. It is caused predominantly by autosomal dominant mutations, mainly in genes encoding cardiac sarcomeric proteins, resulting in diverse phenotypical patterns and a heterogenic clinical course. Unconventional myosin VI (MVI) is one of the proteins important for heart function, as it was shown that a point mutation within MYO6 is associated with left ventricular hypertrophy. Previously, we showed that MVI is expressed in the cardiac muscle, where it localizes to the sarcoplasmic reticulum and intercalated discs. Here, we addressed the mechanisms of its involvement in cardiac dysfunction in Snell's waltzer mice (natural MVI knockouts) during heart development. We showed that heart enlargement was already seen in the E14.5 embryos and newborn animals (P0), and was maintained throughout the examined lifespan (up to 12 months). The higher levels of MVI were observed in the hearts of E14.5 embryos and P0 of control heterozygous mice. A search for the mechanisms behind the observed phenotype revealed several changes, accumulation of which resulted in age-progressing heart dysfunction. The main changes that mostly contribute to this functional impairment are the increase in cardiomyocyte proliferation in newborns, disorganization of intercalated discs, and overexpression of SERCA2 in hearts isolated from 12-month-old mice, indicative of functional alterations of sarcoplasmic reticulum. Also, possible aberrations in the heart vascularization, observed in 12-month-old animals could be additional factors responsible for MVI-associated heart dysfunction.